Dihydropyridinone mgat2 inhibitors for use in the treatment of  metabolic disorders

ABSTRACT

The present invention provides compounds of Formula (I): or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein all of the variables are as defined herein. These compounds are monoacylglycerol acyltransferase type 2 (MGAT2) inhibitors which may be used as medicaments.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Ser.No. 61/949,506, filed Mar. 7, 2014, the entire content of which isincorporated herein by reference.

FIELD OF THE INVENTION

The present invention provides novel heteroaryl dihydropyridinonecompounds, and analogues thereof, which are MGAT2 inhibitors,compositions containing them, and methods of using them, for example,for the treatment or prophylaxis of diabetes, obesity, dyslipidemia andrelated conditions.

BACKGROUND OF THE INVENTION

The prevalence of obesity and diabetes is increasing at an alarmingrate. According to WHO, in 2008, 70% of the U.S. adult population wasoverweight, and among them 33% were obese. Parallel to the explosivenumber of people becoming overweight and obese, in 2008, it wasestimated that 12.3% of the U.S. population had elevated blood glucose[http://www.who.int/diabetes/facts/en/]. The obesity/diabetes epidemicis not unique to the U.S. According to WHO (Fact Sheet No. 312,September 2012), 347 million people worldwide have diabetes. Treatingobesity and improving glycemic control effectively and safely remainmajor challenges for modern medicine.

Monoacylglycerol acyltransferase 2 (MGAT2) has emerged as an attractivetarget for the treatment of obesity and type II diabetes [Yen, C. L. etal., Nat. Med., 15(4):442-446 (2009)]. MGAT2 is highly and selectivelyexpressed in the small intestine where it exerts a pivotal role in themonoacylglycerol-pathway for the absorption of dietary fat. When dietaryfat is ingested, pancreatic lipase digests triglycerides into free fattyacids and 2-monoacylglycerol, which are absorbed by intestinalepithelial enterocytes. Once inside enterocytes, free fatty acids and2-monoacylglycerol are used as building blocks to resynthesizetriglycerides by two sequential acylation steps; first by MGAT and thenby DGAT enzyme reactions. Triglycerides are then incorporated intochylomicrons and secreted into lymph to be utilized as an energy supplyfor the body. MGAT2 knockout mice exhibit a healthy metabolic phenotypeand show resistance to high-fat diet induced obesity, improvement ininsulin sensitivity and decreased fat accumulation in liver and adiposetissue. In addition, genetic deletion of MGAT2 produces mice withincreased levels of GLP1 [Yen, C. L. et al., Nat. Med., 15(4):442-446(2009)]. Taken together, these data show that MGAT2 inhibitors holdpromise to treat metabolic disorders such as obesity, type II diabetesand dyslipidemia.

SUMMARY OF THE INVENTION

The present invention provides heteroaryl dihydropyridinone compounds,and analogues thereof, which are useful as MGAT2 inhibitors, includingstereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs,or solvates thereof.

The present invention also provides processes and intermediates formaking the compounds of the present invention or stereoisomers,tautomers, pharmaceutically acceptable salts, polymorphs, or solvatesthereof.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and at least one of thecompounds of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, polymorphs, or solvates thereof.

The compounds of the invention may be used in the treatment and/orprophylaxis of multiple diseases or disorders associated with MGAT2,such as diabetes, obesity, dyslipidemia and related conditions, such asmicrovascular and macrovascular complications associated with diabetes,cardiovascular diseases, Metabolic Syndrome and its componentconditions, disorders of glucose and lipid metabolism and othermaladies.

The compounds of the invention may be used in therapy.

The compounds of the invention may be used for the manufacture of amedicament for the treatment and/or prophylaxis of multiple diseases ordisorders associated with MGAT2.

The compounds of the invention can be used alone, in combination withother compounds of the present invention, or in combination with one ormore other agent(s).

Other features and advantages of the invention will be apparent from thefollowing detailed description and claims.

DETAILED DESCRIPTION OF THE INVENTION I. Compounds of the Invention

In a first aspect, the present invention provides, inter alia, acompound of Formula (I):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, apolymorph, a solvate or a hydrate thereof, wherein:

ring A is independently a 5- to 6-membered heteroaryl comprising carbonatoms and 1-4 heteroatoms selected from N, NR^(e), O and S; wherein saidheteroaryl is substituted with 0-1 R⁶ and 0-2 R⁷;

R¹ is independently selected from: —(CH₂)_(m)—(C₃₋₆ carbocyclesubstituted with 0-2 R^(b) and 0-2 R^(g)), —(CH₂)_(m)-(5- to 6-memberedheteroaryl comprising carbon atoms and 1-4 heteroatoms selected from N,NR^(e), O and S; wherein said heteroaryl is substituted with 0-1 R^(b)and 0-2 R^(g)), and (a C₁₋₁₂ hydrocarbon chain substituted with 0-3R^(a); wherein said hydrocarbon chain may be straight or branched,saturated or unsaturated);

R² is independently selected from: C₁₋₄ alkyl, C₃₋₄ cycloalkyl, and C₁₋₄haloalkyl;

R³ is independently selected from: H, F, C₁₋₄ alkyl and CN;

R⁴ is independently selected from: H, F, and C₁₋₄ alkyl;

R³ and R⁴ may be combined with the carbon atom to which they areattached to form a 3- to 6-membered carbocycle;

R⁵ is independently selected from: H, halogen, C₁₋₆ alkyl, CN, NO₂,R^(c), NH₂, —(CH₂)_(n)—(X)_(t)—(CH₂)_(m)R^(c), —CONH(C₁₋₆ alkyl), and—NHCOX₁SO₂R^(i);

X is independently selected from the group consisting of O, S, NH, CONH,and NHCO;

X₁ is independently C₁₋₄ hydrocarbon chain optionally substituted withC₁₋₄ alkyl or C₃₋₄ cycloalkyl;

R⁶ is independently selected from: halogen, C₁₋₆ alkyl substituted with0-2 R^(h), C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CO(C₁₋₄ alkyl),—(CH₂)_(m)—C₃₋₆ cycloalkyl, —(CH₂)_(m)—NR^(f)R^(i), CN, OR^(i), SR^(i),and (a 4- to 6-membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, NR^(e), O, and S); R⁷ is independentlyselected from: halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, andC₁₋₄ haloalkoxy;

alternatively, R⁶ and R⁷, together with the carbon atoms to which theyare attached, combine to form a 5- to 6-membered carbocyclic ring or a5- to 6-membered heterocyclic ring comprising carbon atoms and 1-3heteroatoms selected from N, NR^(e), O, and S; wherein said heterocycleis substituted with 0-2 R^(g);

R^(a) is, at each occurrence, independently selected from: halogen, OH,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, N(C₁₋₄ alkyl)₂, COOH, and—(CH₂)_(n)—R^(c);

R^(b) is, at each occurrence, independently selected from: halogen, OH,C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, C₁₋₁₀ haloalkyl, C₁₋₁₀ haloalkoxy, C₁₋₁₀alkylthio, C₁₋₁₀ haloalkylthio, N(C₁₋₄ alkyl)₂, —CONH(C₄₋₂₀ alkyl),—CONH(C₄₋₂₀ haloalkyl), —O(CH₂)_(s)O(C₁₋₆ alkyl), —O(CH₂)_(s)O(C₁₋₆haloalkyl), R^(c), and —(CH₂)_(n)—(O)_(t)—(CH₂)_(m)R^(c);

R^(c) is, at each occurrence, independently selected from: C₃₋₆cycloalkyl substituted with 0-2 R^(d), C₃₋₆ cycloalkenyl substitutedwith 0-2 R^(d), —(CH₂)_(m)-(phenyl substituted with 0-3 R^(d)), and a 5-to 6-membered heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, NR^(e), O, and S; wherein said heterocycle issubstituted with 0-2 R^(d);

R^(d) is, at each occurrence, independently selected from: halogen, OH,CN, NO₂, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy,tetrazolyl, OBn and phenyl;

R^(e) is, at each occurrence, independently selected from: H, C₁₋₈alkyl, C₁₋₈ haloalkyl, —(CH₂)_(n)—C₃₋₆ carbocycle, CO(C₁₋₄ alkyl) andCOBn;

R^(f) is, at each occurrence, independently selected from: H and C₁₋₄alkyl;

R^(g) is, at each occurrence, independently selected from: halogen, C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;

R^(h) is, at each occurrence, independently selected from: OH, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;

R^(i) is, at each occurrence, independently selected from the groupconsisting of C₁₋₄ alkyl, C₃₋₄ cycloalkyl and phenyl;

n, at each occurrence, is independently 0 or 1;

m, at each occurrence, is independently 0, 1, 2, 3, or 4;

s, at each occurrence, is independently 1, 2, or 3; and

t, at each occurrence, is independently 0 or 1.

In a second aspect, the present invention provides a compound of Formula(I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, apolymorph, a solvate or a hydrate thereof, within the scope of the firstaspect, wherein:

R¹ is independently selected from: (C₃₋₆ carbocycle substituted with 0-2R^(b) and 0-2 R^(g)), (a 5- to 6-membered heteroaryl comprising carbonatoms and 1-4 heteroatoms selected from N, NR^(e), O and S; wherein saidheteroaryl is substituted with 0-1 R^(b) and 0-2 R^(g)), and (a C₁₋₁₂hydrocarbon chain substituted with 0-1 R^(a); wherein said hydrocarbonchain may be straight or branched, saturated or unsaturated);

R³ is independently selected from: H, F, C₁₋₄ alkyl and CN;

R⁴ is independently selected from: H, F, and C₁₋₄ alkyl;

R^(b) is, at each occurrence, independently selected from: halogen,C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, C₁₋₁₀ haloalkyl, C₁₋₁₀ haloalkoxy, C₁₋₁₀alkylthio, C₁₋₁₀ haloalkylthio, N(C₁₋₄ alkyl)₂, —CONH(C₄₋₂₀ alkyl),—CONH(C₄₋₂₀ haloalkyl), —O(CH₂)_(s)O(C₁₋₆ alkyl), —O(CH₂)_(s)O(C₁₋₆haloalkyl), R^(c), and —(CH₂)_(n)—(O)_(t)—(CH₂)_(m)R^(c); and

R^(d) is, at each occurrence, independently selected from: halogen, C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, tetrazolyl, OBn andphenyl.

In a third aspect, the present invention provides a compound of Formula(I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, apolymorph, a solvate or a hydrate thereof, within the scope of the firstor second aspect, wherein:

ring A is independently selected from: pyrrolyl, thienyl, thiazolyl,pyrazolyl, pyridyl, and pyrimidinyl; wherein each ring moiety issubstituted with 0-1 R⁶ and 0-2 R⁷; and

alternatively, R⁶ and R⁷, together with the carbon atoms to which theyare attached, combine to form a 6-membered carbocyclic ring.

In a fourth aspect, the present invention includes a compound of Formula(I), or a stereoisomer, a tautomer, a pharmaceutically acceptable salt,a polymorph, a solvate or a hydrate thereof, within the scope of any ofthe above aspects, wherein:

ring A is independently selected from:

R¹ is independently selected from: (phenyl substituted with 1 R^(b) and0-2 R^(g)),

and a C₁₋₁₂ hydrocarbon chain substituted with 0-1 R^(a); wherein saidhydrocarbon chain may be straight or branched, saturated or unsaturated;

R² is independently selected from: C₁₋₄ alkyl and C₁₋₄ haloalkyl;

R³ is independently selected from: H and F;

R⁴ is independently selected from: H and F;

R⁵ is independently selected from: CN, NH₂, —CONH(C₁₋₆ alkyl), R^(c),—CONHSO₂(C₁₋₄ alkyl), —NHCOCH₂SO₂(C₁₋₄ alkyl), —NHCONH(C₁₋₄ alkyl),—OCONH(C₁₋₄ alkyl), and —CONH(Ph substituted with 0-1 R^(g));

R⁶ is independently selected from: halogen, C₁₋₄ alkyl substituted with0-1 N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and C₃₋₆ cycloalkyl;

R⁷ is independently selected from: halogen, C₁₋₄ alkyl and C₁₋₄ alkoxy;

R^(a) is, at each occurrence, independently selected from: halogen, OH,C₁₋₄ alkoxy, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;

R^(b) is, at each occurrence, independently selected from: halogen, OH,C₁₋₈ alkyl, C₁₋₈ alkoxy, C₁₋₈ haloalkyl, and C₁₋₁₀ haloalkoxy;

R^(c) is a 5- to 6-membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, NR^(e), O, and S;

R^(g) is, at each occurrence, independently selected from: halogen, C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;

m, at each occurrence, is independently 0, 1, 2 or 3; and

s, at each occurrence, is independently 1, 2, or 3;

In a fifth aspect, the present invention provides a compound of Formula(IIa) or (IIb):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, apolymorph, a solvate or a hydrate thereof, within the scope of any ofthe above aspects, wherein:

R¹ is independently selected from:

and (a C₁₋₁₂ hydrocarbon chain; wherein said hydrocarbon chain may bestraight or branched, saturated or unsaturated);

R² is independently selected from: CF₃ and CH₃;

R⁵ is independently selected from: CN, tetrazolyl, —CONHSO₂(C₁₋₄ alkyl),—NHCOCH₂SO₂(C₁₋₄ alkyl), and —CONH(4-C₁₋₄ alkoxy-Ph);

R⁶ is independently selected from: halogen, C₁₋₄ alkyl substituted with0-1 N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and C₃₋₆ cycloalkyl;

R^(b) is independently selected from: —O(CH₂)₁₋₆CF₃, and—O(CH₂)₁₋₄CF₂CF₃;

R^(e) is independently selected from: —(CH₂)₁₋₆CF₃, and —(CH₂)₀₋₁(C₃₋₆cycloalkyl); and

R^(g) is independently selected from: halogen and C₁₋₄ alkoxy.

In another aspect, the present invention provides a compound of Formula(IIa):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, apolymorph, a solvate or a hydrate thereof, within the scope of any ofthe above aspects, wherein:

R¹ is independently selected from:

and (a C₁₋₁₂ hydrocarbon chain; wherein said hydrocarbon chain may bestraight or branched, saturated or unsaturated);

R² is independently selected from: CF₃ and CH₃;

R⁵ is independently selected from: CN, tetrazolyl, —CONHSO₂(C₁₋₄ alkyl),—NHCOCH₂SO₂(C₁₋₄ alkyl), and —CONH(4-C₁₋₄ alkoxy-Ph);

R⁶ is independently selected from: halogen, C₁₋₄ alkyl substituted with0-1 N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and C₃₋₆ cycloalkyl;

R^(b) is independently selected from: —O(CH₂)₁₋₆CF₃, and—O(CH₂)₁₋₄CF₂CF₃;

R^(e) is independently selected from: —(CH₂)₁₋₆CF₃, and —(CH₂)₀₋₁(C₃₋₆cycloalkyl); and

R^(g) is independently selected from: halogen and C₁₋₄ alkoxy.

In another aspect, the present invention provides a compound of Formula(IIb):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, apolymorph, a solvate or a hydrate thereof, within the scope of any ofthe above aspects, wherein:

R¹ is independently selected from:

and (a C₁₋₁₂ hydrocarbon chain; wherein said hydrocarbon chain may bestraight or branched, saturated or unsaturated);

R² is independently selected from: CF₃ and CH₃;

R⁵ is independently selected from: CN, tetrazolyl, —CONHSO₂(C₁₋₄ alkyl),—NHCOCH₂SO₂(C₁₋₄ alkyl), and —CONH(4-C₁₋₄ alkoxy-Ph);

R⁶ is independently selected from: halogen, C₁₋₄ alkyl substituted with0-1 N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and C₃₋₆ cycloalkyl;

R^(b) is independently selected from: —O(CH₂)₁₋₆CF₃, and—O(CH₂)₁₋₄CF₂CF₃;

R^(e) is independently selected from: —(CH₂)₁₋₆CF₃, and —(CH₂)₀₋₁(C₃₋₆cycloalkyl); and

R^(g) is independently selected from: halogen and C₁₋₄ alkoxy.

In a sixth aspect, the present invention includes a compound of Formula(I), (IIa) or (IIb), or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, a polymorph, a solvate or a hydrate thereof, within thescope of any of the above aspects, wherein:

R¹ is

In a seventh aspect, the present invention provides a compound selectedfrom the exemplified examples or a stereoisomer, a tautomer, apharmaceutically acceptable salt, or a solvate thereof.

In another aspect, the present invention provides a compound selectedfrom any subset list of compounds or a single compound from theexemplified examples within the scope of any of the above aspects.

In another embodiment, the compounds of the present invention havehMGAT2 IC₅₀ values 1≦μM, using the MGAT2 LCMS assay.

In another embodiment, the compounds of the present invention havehMGAT2 IC₅₀ values 0.5≦μM, using the MGAT2 LCMS assay.

In another embodiment, the compounds of the present invention havehMGAT2 IC₅₀ values 0.1≦μM, using the MGAT2 LCMS assay.

II. Other Embodiments of the Invention

In another embodiment, the present invention provides a compositioncomprising at least one of the compounds of the present invention or astereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atleast one of the compounds of the present invention or a stereoisomer, atautomer, a pharmaceutically acceptable salt, or a solvate thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition, comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof.

In another embodiment, the present invention provides a process formaking a compound of the present invention or a stereoisomer, atautomer, a pharmaceutically acceptable salt, or a solvate thereof.

In another embodiment, the present invention provides an intermediatefor making a compound of the present invention or a stereoisomer, atautomer, a pharmaceutically acceptable salt, or a solvate thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition further comprising additional therapeutic agent(s). In apreferred embodiment, the present invention provides pharmaceuticalcomposition, wherein the additional therapeutic agent is, for example, adipeptidyl peptidase-IV (DPP4) inhibitor (for example a member selectedfrom saxagliptin, sitagliptin, vildagliptin and alogliptin).

In another embodiment, the present invention provides a method for thetreatment of multiple diseases or disorders associated with MGAT2,comprising administering to a patient in need of such treatment atherapeutically effective amount of at least one of the compounds of thepresent invention, alone, or, optionally, in combination with anothercompound of the present invention and/or at least one other type oftherapeutic agent.

Examples of diseases or disorders associated with the activity of theMGAT2 that can be prevented, modulated, or treated according to thepresent invention include, but are not limited to, diabetes,hyperglycemia, impaired glucose tolerance, gestational diabetes, insulinresistance, hyperinsulinemia, nonalcoholic fatty liver disease (NAFLD)including nonalcoholic steatohepatitis (NASH), retinopathy, neuropathy,nephropathy, delayed wound healing, atherosclerosis and its sequelae,abnormal heart function, myocardial ischemia, stroke, MetabolicSyndrome, hypertension, obesity, dyslipidemia, dyslipidemia,hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, lowhigh-density lipoprotein (HDL), high low-density lipoprotein (LDL),non-cardiac ischemia, lipid disorders, and glaucoma.

In another embodiment, the present invention provides a method for thetreatment of diabetes, hyperglycemia, gestational diabetes, obesity,dyslipidemia, and hypertension, comprising administering to a patient inneed of such treatment a therapeutically effective amount of at leastone of the compounds of the present invention, alone, or, optionally, incombination with another compound of the present invention and/or atleast one other type of therapeutic agent.

In another embodiment, the present invention provides a method for thetreatment of diabetes, comprising administering to a patient in need ofsuch treatment a therapeutically effective amount of at least one of thecompounds of the present invention, alone, or, optionally, incombination with another compound of the present invention and/or atleast one other type of therapeutic agent.

In another embodiment, the present invention provides a method for thetreatment of hyperglycemia, comprising administering to a patient inneed of such treatment a therapeutically effective amount of at leastone of the compounds of the present invention, alone, or, optionally, incombination with another compound of the present invention and/or atleast one other type of therapeutic agent.

In another embodiment, the present invention provides a method for thetreatment of obesity, comprising administering to a patient in need ofsuch treatment a therapeutically effective amount of at least one of thecompounds of the present invention, alone, or, optionally, incombination with another compound of the present invention and/or atleast one other type of therapeutic agent.

In another embodiment, the present invention provides a method for thetreatment of dyslipidemia, comprising administering to a patient in needof such treatment a therapeutically effective amount of at least one ofthe compounds of the present invention, alone, or, optionally, incombination with another compound of the present invention and/or atleast one other type of therapeutic agent.

In another embodiment, the present invention provides a method for thetreatment of hypertension, comprising administering to a patient in needof such treatment a therapeutically effective amount of at least one ofthe compounds of the present invention, alone, or, optionally, incombination with another compound of the present invention and/or atleast one other type of therapeutic agent.

In another embodiment, the present invention provides a compound of thepresent invention for use in therapy.

In another embodiment, the present invention provides a compound of thepresent invention for use in therapy for the treatment of multiplediseases or disorders associated with MGAT2.

In another embodiment, the present invention also provides the use of acompound of the present invention for the manufacture of a medicamentfor the treatment of multiple diseases or disorders associated withMGAT2.

In another embodiment, the present invention provides a method for thetreatment of multiple diseases or disorders associated with MGAT2,comprising administering to a patient in need thereof a therapeuticallyeffective amount of a first and second therapeutic agent, wherein thefirst therapeutic agent is a compound of the present invention.Preferably, the second therapeutic agent, for example, dipeptidylpeptidase-IV (DPP4) inhibitor (for example a member selected fromsaxagliptin, sitagliptin, vildagliptin, linagliptin and alogliptin).

In another embodiment, the present invention provides a combinedpreparation of a compound of the present invention and additionaltherapeutic agent(s) for simultaneous, separate or sequential use intherapy.

In another embodiment, the present invention provides a combinedpreparation of a compound of the present invention and additionaltherapeutic agent(s) for simultaneous, separate or sequential use in thetreatment of multiple diseases or disorders associated with MGAT2.

Where desired, the compound of the present invention may be used incombination with one or more other types of anti-diabetic agents and/orone or more other types of therapeutic agents which may be administeredorally in the same dosage form, in a separate oral dosage form or byinjection. The other type of anti-diabetic agent that may be optionallyemployed in combination with the MGAT2 inhibitor of the presentinvention may be one, two, three or more anti-diabetic agents oranti-hyperglycemic agents which may be administered orally in the samedosage form, in a separate oral dosage form, or by injection to producean additional pharmacological benefit.

The anti-diabetic agents used in the combination with the MGAT2inhibitor of the present invention include, but are not limited to,insulin secretagogues or insulin sensitizers, other MGAT2 inhibitors, orother anti-diabetic agents. These agents include, but are not limitedto, dipeptidyl peptidase IV (DPP4) inhibitors (for example, sitagliptin,saxagliptin, alogliptin, linagliptin and vildagliptin), biguanides (forexample, metformin and phenformin), sulfonyl ureas (for example,glyburide, glimepiride and glipizide), glucosidase inhibitors (forexample, acarbose, miglitol), PPARγ agonists such as thiazolidinediones(for example, rosiglitazone and pioglitazone), PPAR α/γ dual agonists(for example, muraglitazar, tesaglitazar and aleglitazar), glucokinaseactivators, GPR40 receptor modulators (e.g., TAK-875), GPR119 receptormodulators (for example, MBX-2952, PSN821, and APD597), sodium-glucosetransporter-2 (SGLT2) inhibitors (for example, dapagliflozin,canagliflozin and remagliflozin), 11β-HSD-1 inhibitors (for exampleMK-0736, BI35585, BMS-823778, and LY2523199), amylin analogs such aspramlintide, leptin signaling modulators (for example, metreleptin),and/or insulin.

The MGAT2 inhibitor of the present invention may also be optionallyemployed in combination with one or more hypophagic and/or weight-lossagents such as diethylpropion, phendimetrazine, phentermine, orlistat,sibutramine, lorcaserin, pramlintide, topiramate, MCHR1 receptorantagonists, oxyntomodulin, naltrexone, Amylin peptide, NPY Y5 receptormodulators, NPY Y2 receptor modulators, NPY Y4 receptor modulators,cetilistat, 5HT2c receptor modulators, and the like. The compounds ofthe present invention may also be employed in combination with anagonist of the glucagon-like peptide-1 receptor (GLP-1 R), such asexenatide, liraglutide, GPR-1(1-36) amide, GLP-1(7-36) amide,GLP-1(7-37), which may be administered via injection, intranasal, or bytransdermal or buccal devices.

The MGAT2 inhibitor of the present invention may also be optionallyemployed in combination with one or more other types of therapeuticagents, such as DGAT inhibitors, LDL lowering drugs such as statins(inhibitors of HMG CoA reductase) or inhibitors of cholesterolabsorption, modulators of PCSK9, drugs that increase HDL such as CETPinhibitors.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of preferred aspects of theinvention noted herein. It is understood that any and all embodiments ofthe present invention may be taken in conjunction with any otherembodiment or embodiments to describe additional embodiments. It is alsounderstood that each individual element of the embodiments is its ownindependent embodiment. Furthermore, any element of an embodiment ismeant to be combined with any and all other elements from any embodimentto describe an additional embodiment.

III. Chemistry

Throughout the specification and the appended claims, a given chemicalformula or name shall encompass all stereo and optical isomers andracemates thereof where such isomers exist. The term “stereoisomer(s)”refers to compound(s) which have identical chemical constitution, butdiffer with regard to the arrangement of the atoms or groups in space.Unless otherwise indicated, all chiral (enantiomeric and diastereomeric)and racemic forms are within the scope of the invention. The term“chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner. The terms “racemic mixture” and “racemate” refer to anequimolar mixture of two enantiomeric species, devoid of opticalactivity.

Many geometric isomers of C═C double bonds, C═N double bonds, ringsystems, and the like can also be present in the compounds, and all suchstable isomers are contemplated in the present invention. Cis- andtrans- (or E- and Z-) geometric isomers of the compounds of the presentinvention are described and may be isolated as a mixture of isomers oras separated isomeric forms.

The present compounds can be isolated in optically active or racemicforms. Optically active forms may be prepared by resolution of racemicforms or by synthesis from optically active starting materials. Allprocesses used to prepare compounds of the present invention andintermediates made therein are considered to be part of the presentinvention. When enantiomeric or diastereomeric products are prepared,they may be separated by conventional methods, for example, bychromatography or fractional crystallization.

Depending on the process conditions the end products of the presentinvention are obtained either in free (neutral) or salt form. Both thefree form and the salts of these end products are within the scope ofthe invention. If so desired, one form of a compound may be convertedinto another form. A free base or acid may be converted into a salt; asalt may be converted into the free compound or another salt; a mixtureof isomeric compounds of the present invention may be separated into theindividual isomers. Compounds of the present invention, free form andsalts thereof, may exist in multiple tautomeric forms, in which hydrogenatoms are transposed to other parts of the molecules and the chemicalbonds between the atoms of the molecules are consequently rearranged. Itshould be understood that all tautomeric forms, insofar as they mayexist, are included within the invention.

Unless otherwise indicated, any heteroatom with unsatisfied valences isassumed to have hydrogen atoms sufficient to satisfy the valences.

As used herein, the term “alkyl” or “alkylene” is intended to includeboth branched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. For examples, “C₁ to C₁₂alkyl” or “C₁₋₁₂ alkyl” (or alkylene), is intended to include C₁, C₂,C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁ and C₁₂ alkyl groups; “C₄ to C₁₈alkyl” or “C₄₋₁₈ alkyl” (or alkylene), is intended to include C₄, C₅,C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃, C₁₄, C₁₅, C₁₆, C₁₇, and C₁₈ alkylgroups. Additionally, for example, “C₁ to C₆ alkyl” or “C₁₋₆ alkyl”denotes alkyl having 1 to 6 carbon atoms. Alkyl group can beunsubstituted or substituted with at least one hydrogen being replacedby another chemical group. Example alkyl groups include, but are notlimited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl andisopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), and pentyl (e.g.,n-pentyl, isopentyl, neopentyl). When “C₀ alkyl” or “C₀ alkylene” isused, it is intended to denote a direct bond.

“Alkenyl” or “alkenylene” is intended to include hydrocarbon chains ofeither straight or branched configuration having the specified number ofcarbon atoms and one or more, preferably one to two, carbon-carbondouble bonds that may occur in any stable point along the chain. Forexample, “C₂ to C₆ alkenyl” or “C₂₋₆ alkenyl” (or alkenylene), isintended to include C₂, C₃, C₄, C₅, and C₆ alkenyl groups. Examples ofalkenyl include, but are not limited to, ethenyl, 1-propenyl,2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3, pentenyl, 4-pentenyl,2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and4-methyl-3-pentenyl.

“Alkynyl” or “alkynylene” is intended to include hydrocarbon chains ofeither straight or branched configuration having one or more, preferablyone to three, carbon-carbon triple bonds that may occur in any stablepoint along the chain. For example, “C₂ to C₆ alkynyl” or “C₂₋₆ alkynyl”(or alkynylene), is intended to include C₂, C₃, C₄, C₅, and C₆ alkynylgroups; such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

When the term “hydrocarbon chain” is used, it is intended to include“alkyl”, “alkenyl” and “alkynyl”, unless otherwise specified.

The term “alkoxy” or “alkyloxy” refers to an —O-alkyl group. Forexample, “C₁ to C₆ alkoxy” or “C₁₋₆ alkoxy” (or alkyloxy), is intendedto include C₁, C₂, C₃, C₄, C₅, and C₆ alkoxy groups. Example alkoxygroups include, but are not limited to, methoxy, ethoxy, propoxy (e.g.,n-propoxy and isopropoxy), and t-butoxy. Similarly, “alkylthio” or“thioalkoxy” represents an alkyl group as defined above with theindicated number of carbon atoms attached through a sulphur bridge; forexample methyl-S— and ethyl-S—.

“Halo” or “halogen” includes fluoro, chloro, bromo, and iodo.“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with 1 or more halogens. Examples of haloalkylinclude, but are not limited to, fluoromethyl, difluoromethyl,trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl,2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examplesof haloalkyl also include “fluoroalkyl” that is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms, substituted with 1 or morefluorine atoms.

“Haloalkoxy” or “haloalkyloxy” represents a haloalkyl group as definedabove with the indicated number of carbon atoms attached through anoxygen bridge. For example, “C₁₋₆ haloalkoxy”, is intended to includeC₁, C₂, C₃, C₄, C₅, and C₆ haloalkoxy groups. Examples of haloalkoxyinclude, but are not limited to, trifluoromethoxy,2,2,2-trifluoroethoxy, and pentafluorothoxy. Similarly, “haloalkylthio”or “thiohaloalkoxy” represents a haloalkyl group as defined above withthe indicated number of carbon atoms attached through a sulphur bridge;for example trifluoromethyl-S—, and pentafluoroethyl-S—.

The term “cycloalkyl” refers to cyclized alkyl groups, including mono-,bi- or poly-cyclic ring systems. For example, “C₃ to C₆ cycloalkyl” or“C₃₋₆ cycloalkyl” is intended to include C₃, C₄, C₅, and C₆ cycloalkylgroups. Example cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl.Branched cycloalkyl groups such as 1-methylcyclopropyl and2-methylcyclopropyl are included in the definition of “cycloalkyl”. Theterm “cycloalkenyl” refers to cyclized alkenyl groups. C₄₋₆ cycloalkenylis intended to include C₄, C₅, and C₆ cycloalkenyl groups. Examplecycloalkenyl groups include, but are not limited to, cyclobutenyl,cyclopentenyl, and cyclohexenyl.

As used herein, “carbocycle”, “carbocyclyl”, or “carbocyclic residue” isintended to mean any stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclicor bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic ortricyclic ring, any of which may be saturated, partially unsaturated,unsaturated or aromatic. Examples of such carbocycles include, but arenot limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl,cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl,adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane(decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl,adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As shownabove, bridged rings are also included in the definition of carbocycle(e.g., [2.2.2]bicyclooctane). Preferred carbocycles, unless otherwisespecified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,indanyl, and tetrahydronaphthyl. When the term “carbocycle” is used, itis intended to include “aryl”. A bridged ring occurs when one or more,preferably one to three, carbon atoms link two non-adjacent carbonatoms. Preferred bridges are one or two carbon atoms. It is noted that abridge always converts a monocyclic ring into a tricyclic ring. When aring is bridged, the substituents recited for the ring may also bepresent on the bridge.

As used herein, the term “bicyclic carbocycle” or “bicyclic carbocyclicgroup” is intended to mean a stable 9- or 10-membered carbocyclic ringsystem that contains two fused rings and consists of carbon atoms. Ofthe two fused rings, one ring is a benzo ring fused to a second ring;and the second ring is a 5- or 6-membered carbon ring which issaturated, partially unsaturated, or unsaturated. The bicycliccarbocyclic group may be attached to its pendant group at any carbonatom which results in a stable structure. The bicyclic carbocyclic groupdescribed herein may be substituted on any carbon if the resultingcompound is stable. Examples of a bicyclic carbocyclic group are, butnot limited to, naphthyl, 1,2-dihydronaphthyl,1,2,3,4-tetrahydronaphthyl, and indanyl.

“Aryl” groups refer to monocyclic or bicyclic aromatic hydrocarbons,including, for example, phenyl, and naphthyl. Aryl moieties are wellknown and described, for example, in Lewis, R. J., ed., Hawley'sCondensed Chemical Dictionary, 15th Edition, John Wiley & Sons, Inc.,New York (2007). “C₆₋₁₀ aryl” refers to phenyl and naphthyl.

The term “benzyl”, as used herein, refers to a methyl group on which oneof the hydrogen atoms is replaced by a phenyl group.

As used herein, the term “heterocycle”, “heterocyclyl”, or “heterocyclicgroup” is intended to mean a stable 3-, 4-, 5-, 6-, or 7-memberedmonocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-memberedpolycyclic heterocyclic ring that is saturated, partially unsaturated,or fully unsaturated, and that contains carbon atoms and 1, 2, 3 or 4heteroatoms independently selected from the group consisting of N, O andS; and including any polycyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The nitrogen and sulfurheteroatoms may optionally be oxidized (i.e., N→O and S(O)_(p), whereinp is 0, 1 or 2). The nitrogen atom may be substituted or unsubstituted(i.e., N or NR wherein R is H or another substituent, if defined). Theheterocyclic ring may be attached to its pendant group at any heteroatomor carbon atom that results in a stable structure. The heterocyclicrings described herein may be substituted on carbon or on a nitrogenatom if the resulting compound is stable. A nitrogen in the heterocyclemay optionally be quaternized. It is preferred that when the totalnumber of S and O atoms in the heterocycle exceeds 1, then theseheteroatoms are not adjacent to one another. It is preferred that thetotal number of S and O atoms in the heterocycle is not more than 1.When the term “heterocycle” is used, it is intended to includeheteroaryl.

Examples of heterocycles include, but are not limited to, acridinyl,azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, imidazolopyridinyl, indolenyl,indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl,methylenedioxyphenyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolopyridinyl, oxazolidinylperimidinyl, oxindolyl,pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl,pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl,pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl,pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl,2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thiazolopyridinyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Alsoincluded are fused ring and spiro compounds containing, for example, theabove heterocycles.

Examples of 5- to 10-membered heterocycles include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl,oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, triazolyl, benzimidazolyl, 1H-indazolyl, benzofuranyl,benzothiofuranyl, benztetrazolyl, benzotriazolyl, benzisoxazolyl,benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl,benzisothiazolyl, isatinoyl, isoquinolinyl, octahydroisoquinolinyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, isoxazolopyridinyl,quinazolinyl, quinolinyl, isothiazolopyridinyl, thiazolopyridinyl,oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl.

Examples of 5- to 6-membered heterocycles include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl,oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, and triazolyl. Also included are fused ring and spirocompounds containing, for example, the above heterocycles.

As used herein, the term “bicyclic heterocycle” or “bicyclicheterocyclic group” is intended to mean a stable 9- or 10-memberedheterocyclic ring system which contains two fused rings and consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, O and S. Of the two fused rings, one ring isa 5- or 6-membered monocyclic aromatic ring comprising a 5-memberedheteroaryl ring, a 6-membered heteroaryl ring or a benzo ring, eachfused to a second ring. The second ring is a 5- or 6-membered monocyclicring which is saturated, partially unsaturated, or unsaturated, andcomprises a 5-membered heterocycle, a 6-membered heterocycle or acarbocycle (provided the first ring is not benzo when the second ring isa carbocycle).

The bicyclic heterocyclic group may be attached to its pendant group atany heteroatom or carbon atom which results in a stable structure. Thebicyclic heterocyclic group described herein may be substituted oncarbon or on a nitrogen atom if the resulting compound is stable. It ispreferred that when the total number of S and O atoms in the heterocycleexceeds 1, then these heteroatoms are not adjacent to one another. It ispreferred that the total number of S and O atoms in the heterocycle isnot more than 1.

Examples of a bicyclic heterocyclic group are, but not limited to,quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl,isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl,1,2,3,4-tetrahydro-quinoxalinyl, and 1,2,3,4-tetrahydro-quinazolinyl.

As used herein, the term “aromatic heterocyclic group” or “heteroaryl”is intended to mean stable monocyclic and polycyclic aromatichydrocarbons that include at least one heteroatom ring member such assulfur, oxygen, or nitrogen. Heteroaryl groups include, withoutlimitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl,pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl,isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl,benzodioxolanyl, and benzodioxane. Heteroaryl groups are substituted orunsubstituted. The nitrogen atom is substituted or unsubstituted (i.e.,N or NR wherein R is H or another substituent, if defined). The nitrogenand sulfur heteroatoms may optionally be oxidized (i.e., N→O andS(O)_(p), wherein p is 0, 1 or 2).

Examples of 5- to 6-membered heteroaryls include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,imidazolyl, imidazolidinyl, tetrazolyl, isoxazolyl, oxazolyl,oxadiazolyl, oxazolidinyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, and triazolyl.

Bridged rings are also included in the definition of heterocycle. Abridged ring occurs when one or more, preferably one to three, atoms(i.e., C, O, N, or S) link two non-adjacent carbon or nitrogen atoms.Examples of bridged rings include, but are not limited to, one carbonatom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and acarbon-nitrogen group. It is noted that a bridge always converts amonocyclic ring into a tricyclic ring. When a ring is bridged, thesubstituents recited for the ring may also be present on the bridge.

The term “counter ion” is used to represent a negatively charged speciessuch as chloride, bromide, hydroxide, acetate, and sulfate or apositively charged species such as sodium (Na+), potassium (K+),ammonium (R_(n)NH_(m)+ where n=0-4 and m=0-4) and the like.

When a dotted ring is used within a ring structure, this indicates thatthe ring structure may be saturated, partially saturated or unsaturated.

As used herein, the term “amine protecting group” means any group knownin the art of organic synthesis for the protection of amine groups whichis stable to an ester reducing agent, a disubstituted hydrazine, R4-Mand R7-M, a nucleophile, a hydrazine reducing agent, an activator, astrong base, a hindered amine base and a cyclizing agent. Such amineprotecting groups fitting these criteria include those listed in Wuts,P. G. M. et al., Protecting Groups in Organic Synthesis, Fourth Edition,Wiley (2007) and The Peptides: Analysis, Synthesis, Biology, Vol. 3,Academic Press, New York (1981), the disclosure of which is herebyincorporated by reference. Examples of amine protecting groups include,but are not limited to, the following: (1) acyl types such as formyl,trifluoroacetyl, phthalyl, and p-toluenesulfonyl; (2) aromatic carbamatetypes such as benzyloxycarbonyl (Cbz) and substitutedbenzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and9-fluorenylmethyloxycarbonyl (Fmoc); (3) aliphatic carbamate types suchas tert-butyloxycarbonyl (Boc), ethoxycarbonyl,diisopropylmethoxycarbonyl, and allyloxycarbonyl; (4) cyclic alkylcarbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl;(5) alkyl types such as triphenylmethyl and benzyl; (6) trialkylsilanesuch as trimethylsilane; (7) thiol containing types such asphenylthiocarbonyl and dithiasuccinoyl; and (8) alkyl types such astriphenylmethyl, methyl, and benzyl; and substituted alkyl types such as2,2,2-trichloroethyl, 2-phenylethyl, and t-butyl; and trialkylsilanetypes such as trimethylsilane.

As referred to herein, the term “substituted” means that at least onehydrogen atom is replaced with a non-hydrogen group, provided thatnormal valencies are maintained and that the substitution results in astable compound. Ring double bonds, as used herein, are double bondsthat are formed between two adjacent ring atoms (e.g., C═C, C═N, orN═N).

In cases wherein there are nitrogen atoms (e.g., amines) on compounds ofthe present invention, these may be converted to N-oxides by treatmentwith an oxidizing agent (e.g., mCPBA and/or hydrogen peroxides) toafford other compounds of this invention. Thus, shown and claimednitrogen atoms are considered to cover both the shown nitrogen and itsN-oxide (N→O) derivative.

When any variable occurs more than one time in any constituent orformula for a compound, its definition at each occurrence is independentof its definition at every other occurrence. Thus, for example, if agroup is shown to be substituted with 0-3 R, then said group mayoptionally be substituted with up to three R groups, and at eachoccurrence R is selected independently from the definition of R.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom in whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent.

Combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms that are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, and/or other problem or complication,commensurate with a reasonable benefit/risk ratio.

Compounds of the present invention can form salts which are also withinthe scope of this invention. Unless otherwise indicated, reference to aninventive compound is understood to include reference to one or moresalts thereof. Pharmaceutically acceptable salts are preferred. However,other salts may be useful, e.g., in isolation or purification stepswhich may be employed during preparation, and thus, are contemplatedwithin the scope of the invention.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic groups such as amines; and alkali or organic saltsof acidic groups such as carboxylic acids. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, andnitric; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, andisethionic, and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Allen, L. V., Jr.,ed., Remington: The Science and Practice of Pharmacy, 22nd Edition,Pharmaceutical Press, London, UK (2012), the disclosure of which ishereby incorporated by reference.

In addition, compounds of formula I may have prodrug forms. Any compoundthat will be converted in vivo to provide the bioactive agent (i.e., acompound of formula I) is a prodrug within the scope and spirit of theinvention. Various forms of prodrugs are well known in the art. Forexamples of such prodrug derivatives, see:

a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985), and Widder,K. et al., eds., Methods in Enzymology, 112:309-396, Academic Press(1985);

b) Bundgaard, H., Chapter 5, “Design and Application of Prodrugs”, ATextbook of Drug Design and Development, pp. 113-191, Krogsgaard-Larsen,P. et al., eds., Harwood Academic Publishers (1991);

c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992);

d) Bundgaard, H. et al., J. Pharm. Sci., 77:285 (1988);

e) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984); and

f) Rautio, J., ed., Prodrugs and Targeted Delivery (Methods andPrinciples in Medicinal Chemistry), Vol. 47, Wiley-VCH (2011).

Compounds containing a carboxy group can form physiologicallyhydrolyzable esters that serve as prodrugs by being hydrolyzed in thebody to yield formula I compounds per se. Such prodrugs are preferablyadministered orally since hydrolysis in many instances occursprincipally under the influence of the digestive enzymes. Parenteraladministration may be used where the ester per se is active, or in thoseinstances where hydrolysis occurs in the blood. Examples ofphysiologically hydrolyzable esters of compounds of formula I includeC₁₋₆alkyl, C₁₋₆alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl,methoxymethyl, C₁₋₆ alkanoyloxy-C₁₋₆alkyl (e.g., acetoxymethyl,pivaloyloxymethyl or propionyloxymethyl),C₁₋₆alkoxycarbonyloxy-C₁₋₆alkyl (e.g., methoxycarbonyl-oxymethyl orethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl), and other well knownphysiologically hydrolyzable esters used, for example, in the penicillinand cephalosporin arts. Such esters may be prepared by conventionaltechniques known in the art.

Preparation of prodrugs is well known in the art and described in, forexample, King, F. D., ed., Medicinal Chemistry: Principles and Practice,The Royal Society of Chemistry, Cambridge, UK (Second Edition,reproduced, 2006); Testa, B. et al., Hydrolysis in Drug and ProdrugMetabolism. Chemistry, Biochemistry and Enzymology, VCHA and Wiley-VCH,Zurich, Switzerland (2003); Wermuth, C. G., ed., The Practice ofMedicinal Chemistry, Third Edition, Academic Press, San Diego, Calif.(2008).

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include deuteriumand tritium. Isotopes of carbon include ¹³C and ¹⁴C.Isotopically-labeled compounds of the invention can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described herein, using an appropriateisotopically-labeled reagent in place of the non-labeled reagentotherwise employed.

The term “solvate” means a physical association of a compound of thisinvention with one or more solvent molecules, whether organic orinorganic. This physical association includes hydrogen bonding. Incertain instances the solvate will be capable of isolation, for examplewhen one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. The solvent molecules in the solvatemay be present in a regular arrangement and/or a non-orderedarrangement. The solvate may comprise either a stoichiometric ornonstoichiometric amount of the solvent molecules. “Solvate” encompassesboth solution-phase and isolable solvates. Exemplary solvates include,but are not limited to, hydrates, ethanolates, methanolates, andisopropanolates. Methods of solvation are generally known in the art.

As used herein, “polymorph(s)” refer to crystalline form(s) having thesame chemical structure/composition but different spatial arrangementsof the molecules and/or ions forming the crystals. Compounds of thepresent invention can be provided as amorphous solids or crystallinesolids. Lyophilization can be employed to provide the compounds of thepresent invention as a solid.

All measurements are subject to experimental error and are within thecontemplation of the invention.

When the invention is described or characterized by any of the disclosedfigures or tables, it is understood that all variations withinlimitations and/or error margins of the experiments and technology arecontemplated.

Abbreviations as used herein, are defined as follows: “1 x” for once, “2x” for twice, “3 x” for thrice, “° C.” for degrees Celsius, “eq” forequivalent or equivalents, “g” for gram or grams, “mg” for milligram ormilligrams, “L” for liter or liters, “mL” for milliliter or milliliters,“μL” for microliter or microliters, “N” for normal, “M” for molar,“mmol” for millimole or millimoles, “min” for minute or min, “h” forhour or h, “rt” for room temperature, “RT” for retention time, “atm” foratmosphere, “psi” for pounds per square inch, “conc.” for concentrate,“aq” for “aqueous”, “sat” or “sat'd” for saturated, “MW” for molecularweight, “mp” for melting point, “MS” or “Mass Spec” for massspectrometry, “ESI” for electrospray ionization mass spectroscopy, “HR”for high resolution, “HRMS” for high resolution mass spectrometry,“LCMS” for liquid chromatography mass spectrometry, “HPLC” for highpressure liquid chromatography, “RP HPLC” for reverse phase HPLC, “TLC”or “tlc” for thin layer chromatography, “NMR” for nuclear magneticresonance spectroscopy, “nOe” for nuclear Overhauser effectspectroscopy, “H” for proton, “δ” for delta, “s” for singlet, “d” fordoublet, “t” for triplet, “q” for quartet, “m” for multiplet, “br” forbroad, “Hz” for hertz, and “α”, “β”, “R”, “S”, “E”, “Z” and “ee” arestereochemical designations familiar to one skilled in the art.

Me methylEt ethylPr propyli-Pr isopropylBu butyli-Bu isobutylt-Bu tert-butylPh phenylBn benzylHex hexanesMeOH methanolEtOH ethanoli-PrOH or IPA isopropanolAcOH or HOAc acetic acidAg₂CO₃ silver carbonateAgOAc silver acetateCDCl₃ deutero-chloroformCHCl₃ chloroformcDNA complementary DNADCC N,N′-dicyclohexylcarbodiimideDIAD diisopropyl azodicarboxylateDMA dimethylamineDME dimethyletherDMF dimethyl formamideDMSO dimethyl sulfoxideDMAP 4-dimethylaminopyridineEDTA ethylenediaminetetraacetic acidEtOAc ethyl acetateEt₂O diethyl etherAlCl₃ aluminum chlorideBoc tert-butyloxycarbonylCH₂Cl₂ dichloromethaneCH₃CN or ACN acetonitrileCs₂CO₃ cesium carbonateHCl hydrochloric acidH₂SO₄ sulfuric acidK₂CO₃ potassium carbonateKCN potassium cyanidemCPBA or m-CPBA meta-chloroperbenzoic acidPd/C palladium on carbonPhSO₂Cl benzenesulfonyl chloridei-Pr₂NEt diisopropylethylaminePS polystyrene

SFC Supercritical Fluid Chromatography

SiO₂ silica oxideSnCl₂ tin(II) chlorideTBAT tetrabutylammonium triphenydifluorosilicateTEA triethylamineTFA trifluoroacetic acidTHF tetrahydrofuranKOAc potassium acetateMgSO₄ magnesium sulfateNaCl sodium chlorideNaH sodium hydrideNaHCO₃ sodium bicarbonateNaOH sodium hydroxideNa₂SO₃ sodium sulfiteNa₂SO₄ sodium sulfateNH₃ ammoniaNH₄Cl ammonium chlorideNH₄OH ammonium hydroxideLG leaving groupPd₂dba₃ tris(dibenzylideneacetone)dipalladium(0)SELECTFLUOR® N-fluoro-N′-methyl-triethylenediaminebis(tetrafluoroborate)

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis. The compoundsof the present invention can be synthesized using the methods describedbelow, together with synthetic methods known in the art of syntheticorganic chemistry, or by variations thereon as appreciated by thoseskilled in the art. Preferred methods include, but are not limited to,those described below. The reactions are performed in a solvent orsolvent mixture appropriate to the reagents and materials employed andsuitable for the transformations being effected. It will be understoodby those skilled in the art of organic synthesis that the functionalitypresent on the molecule should be consistent with the transformationsproposed. This will sometimes require a judgment to modify the order ofthe synthetic steps or to select one particular process scheme overanother in order to obtain a desired compound of the invention.

The novel compounds of this invention may be prepared using thereactions and techniques described in this section. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and workup procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. Restrictions to the substituents that are compatiblewith the reaction conditions will be readily apparent to one skilled inthe art and alternate methods must then be used.

Synthesis

The compounds of Formula (I) may be prepared by the exemplary processesdescribed in the following schemes and working examples, as well asrelevant published literature procedures that are used by one skilled inthe art. Exemplary reagents and procedures for these reactions appearhereinafter and in the working examples. Protection and de-protection inthe processes below may be carried out by procedures generally known inthe art (see, for example, Wuts, P. G. M. et al., Protecting Groups inOrganic Synthesis, Fourth Edition, Wiley (2007)). General methods oforganic synthesis and functional group transformations are found in:Trost, B. M. et al., eds., Comprehensive Organic Synthesis: Selectivity,Strategy & Efficiency in Modern Organic Chemistry, Pergamon Press, NewYork, N.Y. (1991); Smith, M. B. et al., March's Advanced OrganicChemistry: Reactions, Mechanisms, and Structure, Sixth Edition, Wiley &Sons, New York, N.Y. (2007); Katritzky, A. R. et al., eds.,Comprehensive Organic Functional Groups Transformations II, SecondEdition, Elsevier Science Inc., Tarrytown, N.Y. (2004); Larock, R. C.,Comprehensive Organic Transformations, VCH Publishers, Inc., New York,N.Y. (1999), and references therein.

Compounds of Formula (I), single enantiomer, where R³═R⁴═H, can be madeaccording to Scheme 1. Ketone 1 is stirred with2-methylpropane-2-sulfinamide in the presence of a suitable Lewis acid,such as Ti(OEt)₄, in a solvent such as THF at reflux temperature toprovide imine 2. Other Lewis acids, solvents and temperatures may beused as determined by those skilled in the art. Imine 2 is alkylatedwith ketone 3 in the presence of a base, such as LiHMDS, KHMDS, NaHMDS,or LDA in an aprotic solvent such as THF or ether at a temperatureranging from −78° C. to ambient to provide β-amino ketone 4 as a mixtureof two diastereomers, which can be separated by silica gelchromatography to give the desired isomer 5. Other metal enolates (suchas titanium enolate), solvents, and temperatures may be used asdetermined by those skilled in the art (Tang, T. P. et al., J. Org.Chem., 64:12-13 (1999), J. Org. Chem., 67:7819-7832 (2002)). Preferably,chiral S- or R-2-methylpropane-2-sulfinamide can be optionally used togenerate each of the optically pure enantiomers of imine 2 that canallow for chiral induction to prepare diastereomerically enriched ketone5. In these cases, the product mixture can be further purified by silicagel chromatography to obtain desired products with diastereomeric excessof >97%. β-Sulfinamido ketone 5 thus formed is deprotected using HCl ina suitable solvent such as MeOH to provide β-amino ketone 6. Otherconditions to remove the t-butylsulfinyl group may be employed asdetermined by those skilled in the art. β-Amino ketone 6 is acylatedwith carboxylic acid 7 using conditions described in Scheme 2 to givethe β-keto amide 8. Stirring β-keto amide 8 with a base such as sodiumethoxide in a suitable solvent such as ethanol at room temperatureprovides compounds having Formula (I).

Alternatively, compounds of Formula (I), where R³═R⁴═H, may be madeaccording to Scheme 2. Ketone 1 can be reacted with2-methylpropane-2-sulfinamide in the presence of a suitable Lewis acid,such as Ti(OEt)₄, in a solvent such as THF at a temperature ranging fromambient to reflux to provide imine 2. Other Lewis acids, solvents andtemperatures may be used as determined by those skilled in the art.Imine 2 is alkylated with the enolate of an ester in a suitable aproticsolvent such as THF or ether starting at −78° C. then warming to 0° C.or room temperature to provide protected β-sulfinamido ketone 9 as amixture of two diastereomers, which can be separated by silica gelchromatography to give each individual chiral compound. The generationof the ester enolate is achieved by treating the ester, such as methylacetate, with a suitable base such as LHMDS, KHMDS, NaHMDS, or LDA in anaprotic solvent such as THF or ether at a temperature ranging from −78°C. to ambient. Other metal enolates (such as titanium enolate),solvents, and temperatures may be used as determined by those skilled inthe art (Tang, T. P. et al., J. Org. Chem., 64:12-13 (1999), J. Org.Chem., 67:7819-7832 (2002)). Preferably, chiral S- orR-2-methylpropane-2-sulfinamide can be optionally used to generate eachof the optically pure enantiomers of imine 8 that can allow for chiralinduction to prepare diastereomerically enriched ester 9. In thesecases, the product mixture can be further purified by silica gelchromatography to obtain desired products with diastereomeric excessof >97%. The tert-butyl sulfinyl group of 9 is removed using acids suchas HCl and TFA in a suitable solvent such as MeOH or dioxane to generateamino ester 10. Other conditions to remove the t-butylsulfinyl group maybe employed as determined by those skilled in the art. β-Amino ketone 10is acylated with carboxylic acid 11 to give the β-keto amide 12.Stirring β-keto amide 12 with a base such as sodium ethoxide in asuitable solvent such as ethanol at room temperature to 80° C. providescyclic enol 13. Other conditions can also be used to effect thecyclization as determined by those skilled in the art. Compound 13, whentreated with stoichiometric amount of a chlorinating agent, such asPOCl₃, at elevated temperature in an inert solvent such as toluene, isconverted to mono-chloride 14. Chloride 14 can then react with variousboronic reagents through a Suzuki-type of cross coupling reaction togenerate compounds of Formula (I). The choices of boronic reagents,catalysts, ligands, bases, solvents and temperatures are well documentedin the literature and can be selected appropriately by those skilled inthe art. Alternatively, chloride 14 can react with N containingheterocycles 16 through a nucleophilic substitution reaction to generatecompounds of Formula (I).

Non-commercial αα,α-trifluoroketones 1, where R²═CF₃, may be made fromthe corresponding aldehyde 17 as shown in Scheme 3. Aldehyde 17 isreacted with trimethyl-(trifluoromethyl)silane in the presence of afluoride source, for example cesium fluoride, using a suitable solventsuch dimethoxyethane at room temperature. Other fluoride sources, suchas potassium hydrogen fluoride or tetrabutylammoniumdifluorotriphenylsilicate, and other solvents, such as THF oracetonitrile and methanol, may also be employed. Trifluoromethyl alcohol18 is oxidized using, for example, Dess-Martin periodinane in a suitablesolvent such as CH₂Cl₂.

IV. Biology

In mammals, there are two triglyceride synthesis pathways:glycerol-3-phosphate pathway and monoacylglycerol pathway. The former ismainly responsible for energy storage in the peripheral tissues such asfat, liver, skeletal muscle; the latter is essential for the dietary fatabsorption which takes place in the small intestine. When dietary fat isingested, pancreatic lipase digests triglycerides into free fatty acidsand 2-monoacylglycerol, which are absorbed by intestinal epithelialenterocytes. Once inside enterocytes, free fatty acids and2-monoacylglycerol are used as building blocks to resynthesizetriglycerides by two sequential acylation steps; first by MGAT and thenby DGAT enzyme reactions. Triglycerides are then incorporated intochylomicrons and secreted into lymph to be utilized as an energy supplyfor the body.

Monoacylglycerol acyltransferase 2 (MGAT2) is a membrane-boundacyltransferase that belongs to diacylglycerol acyltransferase 2 (DGAT2)gene family. It is highly and selectively expressed in the smallintestine. Genetic deletion of MGAT2 in mice decreased the rate ofabsorption for the orally ingested triglycerides, indicating that MGAT2plays an important role for the intestinal MGAT/DGAT pathway [Yen, C. L.et al., Nat. Med., 15(4):442-446 (2009); Okawa, M. et al., Biochem.Biophys. Res. Commun., 390(3):377-381 (2009)]. When chronicallychallenged with a high fat diet, in contrast to wild type mice thatbecame obese, MGAT2 knockout mice resisted the impact of high-fatfeeding and had a lower body weight, less adiposity, and less hepaticfat accumulation. In contrast to hyperinsulinemic wild type mice afterhigh-fat challenge, MGAT2 deletion normalizes the insulin level anddecreased fasting glucose. In the glucose tolerance test, they also hadan improved glucose excursion. Consistent with their improved glycemicprofile, MGAT2 knockout mice also had an increased level of GLP1, anincretin gut hormone that profoundly impacts glucose metabolism [Yen, C.L. et al., Nat. Med., 15(4):442-446 (2009)]. Taken together, it isexpected that inhibition of MGAT2 through pharmacological interventionwould provide the same benefit as demonstrated in the knock-out mice,e.g., resistance to weight gain, or conversely, reduction in fat bodymass. In addition, MGAT2 inhibition would lead to an improved insulinsensitivity and glucose metabolism which either leads to a decrease inthe incidence of Type II diabetes, or a treatment of diabetic condition.

It is also desirable and preferable to find compounds with advantageousand improved characteristics compared with known anti-diabetic agents,in one or more of the following categories that are given as examples,and are not intended to be limiting: (a) pharmacokinetic properties,including oral bioavailability, half life, and clearance; (b)pharmaceutical properties; (c) dosage requirements; (d) factors thatdecrease blood drug concentration peak-to-trough characteristics; (e)factors that increase the concentration of active drug at the receptor;(f) factors that decrease the liability for clinical drug-druginteractions; (g) factors that decrease the potential for adverseside-effects, including selectivity versus other biological targets; and(h) improved therapeutic index with less propensity for hypoglycemia.

As used herein, the term “patient” encompasses all mammalian species.

As used herein, the term “subject” refers to any human or non-humanorganism that could potentially benefit from treatment with a MGAT2inhibitor. Exemplary subjects include human beings of any age with riskfactors for metabolic disease. Common risk factors include, but are notlimited to, age, sex, weight, family history, or signs of insulinresistance such as acanthosis nigricans, hypertension, dyslipidemia, orpolycystic ovary syndrome (PCOS).

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)inhibiting the disease-state, i.e., arresting it development; (b)relieving the disease-state, i.e., causing regression of the diseasestate; and/or (c) preventing the disease-state from occurring in amammal, in particular, when such mammal is predisposed to thedisease-state but has not yet been diagnosed as having it.

As used herein, “preventing” or “prevention” cover the preventivetreatment (i.e., prophylaxis and/or risk reduction) of a subclinicaldisease-state in a mammal, particularly in a human, aimed at reducingthe probability of the occurrence of a clinical disease-state. Patientsare selected for preventative therapy based on factors that are known toincrease risk of suffering a clinical disease state compared to thegeneral population. “Prophylaxis” therapies can be divided into (a)primary prevention and (b) secondary prevention. Primary prevention isdefined as treatment in a subject that has not yet presented with aclinical disease state, whereas secondary prevention is defined aspreventing a second occurrence of the same or similar clinical diseasestate.

As used herein, “risk reduction” or “reducing risk” covers therapiesthat lower the incidence of development of a clinical disease state. Assuch, primary and secondary prevention therapies are examples of riskreduction.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention that is effective when administeredalone or in combination to inhibit MGAT2 and/or to prevent or treat thedisorders listed herein. When applied to a combination, the term refersto combined amounts of the active ingredients that result in thepreventive or therapeutic effect, whether administered in combination,serially, or simultaneously.

Assay Methods MGAT LCMS Assay

The MGAT enzyme reactions were performed in Corning FALCON® 96-wellpolypropylene plates, in a total volume of 60 μL of 50 mM potassiumphosphate buffer pH 7.4, containing a final concentration of 100 μM2-oleoylglycerol, 15 μM oleoyl-coenzyme A and 0.0013 μg/μL human ormouse MGAT-2 or 0.0026 μg/μL rat recombinant MGAT-2 membranes expressedin Sf9 cells. Assay plates were run through a fully automated roboticssystem and shaken for 5 seconds every minute for a total 10 minutes. Thereactions were then quenched with 120 μL of ice cold methanol containing1 μg/mL 1,2-distearoyl-rac-glycerol as the internal standard. Plateswere shaken for 2 minutes and spun down to remove protein precipitation.After the spin, samples were transferred to LC/MS compatible PCR plates.For LC/MS analysis, a ThermoFisher Surveyor pump, utilizing a WatersSYMMETRY® C8, 50×2.1 mm column, was used for the chromatography ofenzyme products. The buffer system consists of 0.1% formic acid in waterwith a mobile phase consisting 0.1% formic acid in methanol. The shallowgradient is 90-100% mobile phase in 0.2 min with a total run time of 2.3min. The first 0.5 minutes of each injection was diverted to waste toeliminate the presence of phosphate buffer in the enzymatic reaction.The column was run at 0.6 mL/min and a temperature of 65° C. Massspectrometry analysis of the samples was performed on a ThermoFisherQuantum Triple quad utilizing APCI (+) as the mode of ionization. Datawas acquired in Single Ion Monitoring (SIM) mode analyzing Diolein=m/z603.6 (PRODUCT) and 1,2-distearoyl-rac-glycerol (IS)=m/z 607.6. Theratio of Diolein to internal standard (Peak Area Ratio) is utilized tocalculate IC₅₀ values.

The exemplified Examples disclosed below were tested in the MGAT2 invitro assays described above and were found having MGAT2 inhibitoryactivity. Table 1 below lists human MGAT2 IC₅₀ values measured for thefollowing examples. “NT” denotes “Not tested”.

TABLE 1 Example No. h-MGAT LCMS IC₅₀ (nM) 1 2.5 2 41 3 370 4 0.9 5 7.8 62.2 7 9 8 1.5 9 32 10 >2 μM <10 μM 11 873 12 363 13 19.4 14 72.1 15 14.516 34 17 16.6 18 24.5 19 31.8 20 74.7 21 135 22 1.2 23 2.1 24 22.9 25102 26 43.7 27 185 28 17.6 29 52.1 30 2.7 31 61.9 32 12.6 33 950 34 86.935 11.5 36 79.2 37 12.5 38 34.3 39 16.6 40 6.7 41 73.6 42 3.0 43 20.2 4415.2 45 3.5 46 11.4 47 2.7 48 8.8 49 4.5 50 9.4 51 97.4 52 3.2 53 44.054 1.1 55 7.8 56 0.2 57 1.4 58 2.2 59 1.4 60 137 61 120 62 2.1 63 0.7 641.1 65 8.8 66 0.5 67 97.6 68 30.2 69 148 70 32.3 71 31.5 72 10.3 73 13574 15 75 1.5 76 4.2 77 522

The compounds of the present invention possess activity as inhibitors ofMGAT2, and, therefore, may be used in the treatment of diseasesassociated with MGAT2 activity. Via modulation of MGAT2, the compoundsof the present invention may preferably be employed to modulate, eitherenhance or decrease the production/secretion of insulin and/or guthormones, such as GLP1, GIP, CCK, PYY, PP, Amylin.

Accordingly, the compounds of the present invention can be administeredto mammals, preferably humans, for the treatment of a variety ofconditions and disorders, including, but not limited to, treating,preventing, or slowing the progression of diabetes and relatedconditions, microvascular complications associated with diabetes,macrovascular complications associated with diabetes, cardiovasculardiseases, Metabolic Syndrome and its component conditions, inflammatorydiseases and other maladies. Consequently, it is believed that thecompounds of the present invention may be used in preventing,inhibiting, or treating diabetes, hyperglycemia, impaired glucosetolerance, gestational diabetes, insulin resistance, hyperinsulinemia,retinopathy, neuropathy, nephropathy, wound healing, atherosclerosis andits sequelae (acute coronary syndrome, myocardial infarction, anginapectoris, peripheral vascular disease, intermittent claudication,myocardial ischemia, stroke, heart failure), Metabolic Syndrome,hypertension, obesity, dyslipidemia, hyperlipidemia,hypertriglyceridemia, hypercholesterolemia, low HDL, high LDL, lipiddisorders, PCOS, and glaucoma.

Metabolic Syndrome or “Syndrome X” is described in Ford et al., J. Am.Med. Assoc., 287:356-359 (2002) and Arbeeny et al., Curr. Med.Chem.—Imm., Endoc. & Metab. Agents, 1:1-24 (2001).

V. Pharmaceutical Compositions, Formulations and Combinations

The compounds of this invention can be administered for any of the usesdescribed herein by any suitable means, for example, orally, such astablets, capsules (each of which includes sustained release or timedrelease formulations), pills, powders, granules, elixirs, tinctures,suspensions (including nanosuspensions, microsuspensions, spray-drieddispersions), syrups, and emulsions; sublingually; buccally;parenterally, such as by subcutaneous, intravenous, intramuscular, orintrasternal injection, or infusion techniques (e.g., as sterileinjectable aqueous or non-aqueous solutions or suspensions); nasally,including administration to the nasal membranes, such as by inhalationspray; topically, such as in the form of a cream or ointment; orrectally such as in the form of suppositories. They can be administeredalone, but generally will be administered with a pharmaceutical carrierselected on the basis of the chosen route of administration and standardpharmaceutical practice.

The term “pharmaceutical composition” means a composition comprising acompound of the invention in combination with at least one additionalpharmaceutically acceptable carrier. A “pharmaceutically acceptablecarrier” refers to media generally accepted in the art for the deliveryof biologically active agents to animals, in particular, mammals,including, i.e., adjuvant, excipient or vehicle, such as diluents,preserving agents, fillers, flow regulating agents, disintegratingagents, wetting agents, emulsifying agents, suspending agents,sweetening agents, flavoring agents, perfuming agents, antibacterialagents, antifungal agents, lubricating agents and dispensing agents,depending on the nature of the mode of administration and dosage forms.

Pharmaceutically acceptable carriers are formulated according to anumber of factors well within the purview of those of ordinary skill inthe art. These include, without limitation: the type and nature of theactive agent being formulated; the subject to which the agent-containingcomposition is to be administered; the intended route of administrationof the composition; and the therapeutic indication being targeted.Pharmaceutically acceptable carriers include both aqueous andnon-aqueous liquid media, as well as a variety of solid and semi-soliddosage forms. Such carriers can include a number of differentingredients and additives in addition to the active agent, suchadditional ingredients being included in the formulation for a varietyof reasons, e.g., stabilization of the active agent, binders, etc., wellknown to those of ordinary skill in the art. Descriptions of suitablepharmaceutically acceptable carriers, and factors involved in theirselection, are found in a variety of readily available sources such as,for example, Allen, L. V., Jr. et al., Remington: The Science andPractice of Pharmacy (2 Volumes), 22nd Edition, Pharmaceutical Press(2012).

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to about 5000 mg per day, preferably between about 0.01 toabout 1000 mg per day, and most preferably between about 0.1 to about250 mg per day. Intravenously, the most preferred doses will range fromabout 0.01 to about 10 mg/kg/minute during a constant rate infusion.Compounds of this invention may be administered in a single daily dose,or the total daily dosage may be administered in divided doses of two,three, or four times daily.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, e.g., oral tablets, capsules,elixirs, and syrups, and consistent with conventional pharmaceuticalpractices.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 2000 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.1-95% by weight based on the total weight of the composition.

A typical capsule for oral administration contains at least one of thecompounds of the present invention (250 mg), lactose (75 mg), andmagnesium stearate (15 mg). The mixture is passed through a 60 meshsieve and packed into a No. 1 gelatin capsule.

A typical injectable preparation is produced by aseptically placing atleast one of the compounds of the present invention (250 mg) into avial, aseptically freeze-drying and sealing. For use, the contents ofthe vial are mixed with 2 mL of physiological saline, to produce aninjectable preparation.

The present invention includes within its scope pharmaceuticalcompositions comprising, as an active ingredient, a therapeuticallyeffective amount of at least one of the compounds of the presentinvention, alone or in combination with a pharmaceutical carrier.Optionally, compounds of the present invention can be used alone, incombination with other compounds of the invention, or in combinationwith one or more other therapeutic agent(s), e.g., an anti-diabeticagent or other pharmaceutically active material.

The compounds of the present invention may be employed in combinationwith other MGAT2 inhibitors or one or more other suitable therapeuticagents useful in the treatment of the aforementioned disordersincluding: anti-diabetic agents, anti-hyperglycemic agents,anti-hyperinsulinemic agents, anti-retinopathic agents, anti-neuropathicagents, anti-nephropathic agents, anti-atherosclerotic agents,anti-ischemic agents, anti-hypertensive agents, anti-obesity agents,anti-dyslipidemic agents, anti-dyslipidemic agents, anti-hyperlipidemicagents, anti-hypertriglyceridemic agents, anti-hypercholesterolemicagents, anti-restenotic agents, anti-pancreatic agents, lipid loweringagents, anorectic agents, memory enhancing agents, anti-dementia agents,or cognition promoting agents, appetite suppressants, treatments forheart failure, treatments for peripheral arterial disease andanti-inflammatory agents.

Where desired, the compound of the present invention may be used incombination with one or more other types of anti-diabetic agents and/orone or more other types of therapeutic agents which may be administeredorally in the same dosage form, in a separate oral dosage form or byinjection. The other type of anti-diabetic agent that may be optionallyemployed in combination with the MGAT2 inhibitor of the presentinvention may be one, two, three or more anti-diabetic agents oranti-hyperglycemic agents which may be administered orally in the samedosage form, in a separate oral dosage form, or by injection to producean additional pharmacological benefit.

The anti-diabetic agents used in the combination with the compound ofthe present invention include, but are not limited to, insulinsecretagogues or insulin sensitizers, other MGAT2 inhibitors, or otheranti-diabetic agents. These agents include, but are not limited to,dipeptidyl peptidase IV (DP4) inhibitors (for example, sitagliptin,saxagliptin, alogliptin, vildagliptin and the like), biguanides (forexample, metformin, phenformin and the like), sulfonyl ureas (forexample, glyburide, glimepiride, glipizide and the like), glucosidaseinhibitors (for example, acarbose, miglitol, and the like), PPARγagonists such as thiazolidinediones (for example, rosiglitazone,pioglitazone, and the like), PPAR α/γ dual agonists (for example,muraglitazar, tesaglitazar, aleglitazar, and the like), glucokinaseactivators (as described in Fyfe, M. C. T. et al., Drugs of the Future,34(8):641-653 (2009) and incorporated herein by reference), GPR40receptor modulators, GPR119 receptor modulators (MBX-2952, PSN821,APD597 and the like), SGLT2 inhibitors (dapagliflozin, canagliflozin,remagliflozin and the like), amylin analogs such as pramlintide, and/orinsulin. Reviews of current and emerging therapies for the treatment ofdiabetes can be found in: Mohler, M. L. et al., Medicinal ResearchReviews, 29(1):125-195 (2009), and Mizuno, C. S. et al., CurrentMedicinal Chemistry, 15:61-74 (2008).

The compounds of the present invention may also be optionally employedin combination with agents for treating complication of diabetes. Theseagents include PKC inhibitors and/or AGE inhibitors.

The compounds of the present invention may also be optionally employedin combination with one or more hypophagic agents such asdiethylpropion, phendimetrazine, phentermine, orlistat, sibutramine,lorcaserin, pramlintide, topiramate, MCHR1 receptor antagonists,oxyntomodulin, naltrexone, Amylin peptide, NPY Y5 receptor modulators,NPY Y2 receptor modulators, NPY Y4 receptor modulators, cetilistat,5HT2c receptor modulators, and the like. The compound of structure I mayalso be employed in combination with an agonist of the glucagon-likepeptide-1 receptor (GLP-1 R), such as exenatide, liraglutide,GPR-1(1-36) amide, GLP-1(7-36) amide, GLP-1(7-37) (as disclosed in U.S.Pat. No. 5,614,492 to Habener, the disclosure of which is incorporatedherein by reference), which may be administered via injection,intranasal, or by transdermal or buccal devices. Reviews of current andemerging therapies for the treatment of obesity can be found in:Melnikova, I. et al., Nature Reviews Drug Discovery, 5:369-370 (2006);Jones, D., Nature Reviews: Drug Discovery, 8:833-834 (2009); Obici, S.,Endocrinology, 150(6):2512-2517 (2009); and Elangbam, C. S., Vet.Pathol., 46(1):10-24 (2009).

The compounds of the present invention may also be optionally employedin combination with one or more other types of therapeutic agents, suchas DGAT inhibitors, LDL lowering drugs such as statins (inhibitors ofHMG CoA reductase) or inhibitors of cholesterol absorption, modulatorsof PCSK9, drugs increase HDL such as CETP inhibitors.

The above other therapeutic agents, when employed in combination withthe compounds of the present invention may be used, for example, inthose amounts indicated in the Physicians' Desk Reference, as in thepatents set out above, or as otherwise determined by one of ordinaryskill in the art.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when the compound of the present invention and a secondtherapeutic agent are combined in a single dosage unit they areformulated such that although the active ingredients are combined in asingle dosage unit, the physical contact between the active ingredientsis minimized (that is, reduced). For example, one active ingredient maybe enteric coated. By enteric coating one of the active ingredients, itis possible not only to minimize the contact between the combined activeingredients, but also, it is possible to control the release of one ofthese components in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but rather is released in theintestines. One of the active ingredients may also be coated with amaterial that affects a sustained-release throughout thegastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer, and the other component is also coated with a polymersuch as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) orother appropriate materials as known in the art, in order to furtherseparate the active components. The polymer coating serves to form anadditional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

The compounds of the present invention can be administered alone or incombination with one or more additional therapeutic agents. By“administered in combination” or “combination therapy” it is meant thatthe compound of the present invention and one or more additionaltherapeutic agents are administered concurrently to the mammal beingtreated. When administered in combination, each component may beadministered at the same time or sequentially in any order at differentpoints in time. Thus, each component may be administered separately butsufficiently closely in time so as to provide the desired therapeuticeffect.

The compounds of the present invention are also useful as standard orreference compounds, for example as a quality standard or control, intests or assays involving the MGAT2 enzyme. Such compounds may beprovided in a commercial kit, for example, for use in pharmaceuticalresearch involving MGAT2 or anti-diabetic activity. For example, acompound of the present invention could be used as a reference in anassay to compare its known activity to a compound with an unknownactivity. This would ensure the experimentor that the assay was beingperformed properly and provide a basis for comparison, especially if thetest compound was a derivative of the reference compound. Whendeveloping new assays or protocols, compounds according to the presentinvention could be used to test their effectiveness.

The compounds of the present invention may also be used in diagnosticassays involving MGAT2.

The present invention also encompasses an article of manufacture. Asused herein, article of manufacture is intended to include, but not belimited to, kits and packages. The article of manufacture of the presentinvention, comprises: (a) a first container; (b) a pharmaceuticalcomposition located within the first container, wherein the composition,comprises: a first therapeutic agent, comprising a compound of thepresent invention or a pharmaceutically acceptable salt form thereof;and, (c) a package insert stating that the pharmaceutical compositioncan be used for the treatment and/or prophylaxis of multiple diseases ordisorders associated with MGAT2 (as defined previously). In anotherembodiment, the package insert states that the pharmaceuticalcomposition can be used in combination (as defined previously) with asecond therapeutic agent for the treatment and/or prophylaxis ofmultiple diseases or disorders associated with MGAT2. The article ofmanufacture can further comprise: (d) a second container, whereincomponents (a) and (b) are located within the second container andcomponent (c) is located within or outside of the second container.Located within the first and second containers means that the respectivecontainer holds the item within its boundaries.

The first container is a receptacle used to hold a pharmaceuticalcomposition. This container can be for manufacturing, storing, shipping,and/or individual/bulk selling. First container is intended to cover abottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation),or any other container used to manufacture, hold, store, or distribute apharmaceutical product.

The second container is one used to hold the first container and,optionally, the package insert. Examples of the second containerinclude, but are not limited to, boxes (e.g., cardboard or plastic),crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks.The package insert can be physically attached to the outside of thefirst container via tape, glue, staple, or another method of attachment,or it can rest inside the second container without any physical means ofattachment to the first container. Alternatively, the package insert islocated on the outside of the second container. When located on theoutside of the second container, it is preferable that the packageinsert is physically attached via tape, glue, staple, or another methodof attachment. Alternatively, it can be adjacent to or touching theoutside of the second container without being physically attached.

The package insert is a label, tag, marker, etc. that recitesinformation relating to the pharmaceutical composition located withinthe first container. The information recited will usually be determinedby the regulatory agency governing the area in which the article ofmanufacture is to be sold (e.g., the United States Food and DrugAdministration). Preferably, the package insert specifically recites theindications for which the pharmaceutical composition has been approved.The package insert may be made of any material on which a person canread information contained therein or thereon. Preferably, the packageinsert is a printable material (e.g., paper, plastic, cardboard, foil,adhesive-backed paper or plastic, etc.) on which the desired informationhas been formed (e.g., printed or applied).

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments that are given forillustration of the invention and are not intended to be limitingthereof.

VI. Examples

The following Examples are offered as illustrative, as a partial scopeand particular embodiments of the invention and are not meant to belimiting of the scope of the invention. Abbreviations and chemicalsymbols have their usual and customary meanings unless otherwiseindicated. Unless otherwise indicated, the compounds described hereinhave been prepared, isolated and characterized using the schemes andother methods disclosed herein or may be prepared using the same.

HPLC/MS, Preparatory/Analytical HPLC, and Chiral Separation MethodsEmployed in Characterization or Purification of Examples

Analytical HPLC/MS (unless otherwise noted) was performed on ShimadzuSCL-10A liquid chromatographs and Waters MICROMASS® ZQ MassSpectrometers (Desolvation Gas: Nitrogen; Desolvation Temp. 250° C.; IonSource Temp: 120° C.; Positive Electrospray conditions) using thefollowing methods:

Linear Gradient of 0% to 100% Solvent B over 2 min, with 1 minute holdat 100% B, or

Linear Gradient of 0% to 100% Solvent B over 4 min, with 1 minute holdat 100% B;

UV visualization at 220 nm;

Column: PHENOMENEX® Luna C18 (2) 30 mm×4.6 mm; 5μ particle (heated toTemp. 40° C.);

Flow rate: 1.0 mL/min (2 min gradient) or 0.8 ml/min (4 min gradient);

Solvent A: 10% ACN, 90% water, 0.1% TFA; or, 10% MeOH, 90% water, 0.1%TFA and

Solvent B: 90% ACN, 10% water, 0.1% TFA; or, 90% MeOH, 10% water, 0.1%TFA.

Preparatory HPLC (unless otherwise noted) was performed on a ShimadzuSCL-10A liquid chromatograph with a linear gradient of 20-100% Solvent Bover 10 to 30 min, with either a 2 to 5 min hold at 100% Solvent B asdetermined by on skilled in the art;

UV visualization at 220 nm;

Column: PHENOMENEX® Luna Axia 5μ C18 30×100 mm;

Flow rate: 20 mL/min;

Solvent A: 10% ACN, 90% water, 0.1% TFA; or 10% MeOH, 90% water, 0.1%TFA; and

Solvent B: 90% ACN, 10% water, 0.1% TFA; or 90% MeOH, 10% water, 0.1%TFA.

Preparatory chiral SFC chromatography (unless otherwise noted) wasperformed on a Berger Multigram II SFC chromatograph using one of thefollowing methods:

Preparative Chiral SFC Method A:

Column: CHIRALCEL® OD-H, 30×250 mm ID, 5μ

Flow rate: 90 mL/min, 100 bar BP, 40° C.

Mobile Phase: 15% methanol/85% CO₂

Detector Wavelength: 254 nm

Injection Vol and Sample Solution: 0.5 mL of 4.65 g in 35 mL methanol(133 mg/mL)

Preparative Chiral SFC Method B:

Instrument: Berger SFC MGII (HPW-2501)

Column: CHIRALPAK® IA 25×3 cm ID, 5 μm

Flow rate: 85.0 mL/min

Mobile Phase: 85/15/0.1,CO₂/IPA/DEA, 150 bar

Detector Wavelength: 225 nm (Lamda max)

Sample Prep and Inj. Volume: 300 μL of ˜13 mg/0.5 mL IPA (˜26 mg/mL)

Preparative Chiral SFC Method C:

Column: CHIRALPAK® IA 25×3 cm ID, 5 μm

Flow rate: 90 mL/min

Mobile Phase: 85/15/0.1,CO₂/MeOH/DEA, 150 bar

Detector Wavelength: 270 nm (Lambda max)

Sample Prep and Inj. Volume: 300 μL of ˜90 mg/2 mL MeOH (˜45 mg/mL)

Preparative Chiral SFC Method D:

Flow rate: 40 mL/min, 100 Bar, 35° C.

Mobile Phase: 20% methanol/80% CO₂

Detector Wavelength: 224 nm (Lambda max)

Injection Volume: 300 μL

Sample Preparation: 10 mg dissolved in 0.5 mL MeCN (20 mg/mL);

-   -   17 mg dissolved in 0.5 mL MeCN (34 mg/mL)

Analytical chiral SFC chromatography (unless otherwise noted) wasperformed on an Aurora Analytical SFC or Berger Analytical SFC using oneof the following methods:

Analytical Chiral SFC Method A:

Column: CHIRALCEL® OD-H, 4.6×250 mm ID, 5 μm

Flow rate: 3.0 mL/min, 100 bar BP, 35° C.

Mobile Phase: 15% methanol/85% CO₂

Detector Wavelength: 220 nm

Sample Solution: 1 mg/mL in methanol (concentrated/reconstituted)

Injection Volume: 10 μL

Analytical Chiral SFC Method B:

Column: CHIRALPAK® IA 250×4.6 mm ID, 5 μm

Flow rate: 2.0 mL/min

Mobile Phase: 85/15/0.1, CO₂/IPA/DEA, 150 bar

Detector Wavelength: 225 nm (Lamda max)

Injection Volume: 10 μL

Analytical Chiral SFC Method C:

Column: CHIRALPAK® IA 250×4.6 mm ID, 5 μm

Flow rate: 3.0 mL/min

Mobile Phase: 65/35/0.1, CO₂/MeOH/DEA, 150 bar

Detector Wavelength: 270 nm (Lambda max)

Injection Volume: 10 μL

Analytical Chiral SFC Method D:

Column: CHIRALCEL® OD, 250×4.6 mm ID, 10 μm

Flow rate: 2.0 mL/min, 100 bar, 35° C.

Mobile Phase: 20% Methanol/80% CO₂

Detector Wavelength: 223 nm

Injection Volume: 10 μL

NMR Employed in Characterization of Examples

¹H NMR spectra (unless otherwise noted) were obtained with JEOL® orBruker FOURIER® transform spectrometers operating at 400 MHz or 500 MHz.¹H-nOe experiments were performed in some cases for regiochemistryelucidation with a 400 MHz Bruker FOURIER® Transform spectrometer.

Spectral data are reported as chemical shift (multiplicity, number ofhydrogens, coupling constants in Hz) and are reported in ppm (δ units)relative to either an internal standard (tetramethyl silane=0 ppm) for¹H NMR spectra, or are referenced to the residual solvent peak (2.49 ppmfor CD₃SOCD₂H, 3.30 ppm for CD₂HOD, 1.94 for CHD₂CN, 7.26 ppm for CHCl₃,5.32 ppm for CDHCl₂).

Microwave instrumentation employed in heating reactions.

BIOTAGE® Initiator 2.5, maximum power 400 W, reaction volume range0.2-10 mL. Reactions are run in sealed pressure vessels speciallymanufactured for this instrument.

Intermediate 1(S,E)-2-Methyl-N-(2,2,2-trifluoro-1-(4-(4,4,4-trifluorobutoxy)phenyl)ethylidene)propane-2-sulfinamide

Intermediate 1A. 4-(4,4,4-Trifluorobutoxy)benzaldehyde: To a solution of4-hydroxybenzaldehyde (20 g, 164 mmol) and 4,4,4-trifluorobutan-1-ol (25g, 195 mmol) in anhydrous CH₂Cl₂ (500 mL) at 0° C. under argon was addeda solution of PPh₃ (51.5 g, 196 mmol) in CH₂Cl₂ (200 mL) over 15 min,and then DIAD (36.4 g, 180 mmol) in anhydrous CH₂Cl₂ (150 mL) was addeddropwise. The mixture was stirred at 0° C. for 0.5 h. The reaction waswarmed to rt and stirred for another 3 h. The solvent was removed invacuo and the residue was triturated with CH₂Cl₂ three times to removeinsoluble solids. The combined CH₂Cl₂ washings were concentrated and theresidue was purified by silica gel chromatography (330 g silica gel,eluted with EtOAc in hexanes) to provide Intermediate 1A (27 g, 71%) asa light brown oil. LCMS Anal. Calc'd for C₁₁H₁₁F₃O₂, 232.20. found [M+H]233.0.

Intermediate 1B.2,2,2-Trifluoro-1-(4-(4,4,4-trifluorobutoxy)phenyl)ethanol: To thesolution of Intermediate 1A (26.7 g, 114 mmol) andtrimethyl(trifluoromethyl)silane (16.9 g, 119 mmol) in anhydrous DME(112 mL) was added CsF (500 mg, 3.29 mmol). The reaction was stirred atrt for 16 h. To the mixture was added 4 N aq. HCl (114 mL) and thereaction was stirred at rt for 2.5 h. The reaction was diluted withEtOAc (300 mL) and washed with water, sat'd aq. NaHCO₃, sat'd aq. NaCl,dried over anhydrous MgSO₄, filtered and concentrated to provideIntermediate 1B (42.5 g, 122%) as an oil. The crude product was usedwithout further purification. LCMS Anal. Calc'd for C₁₂H₁₂F₆O₂, 302.21.found [M−H] 301.2.

Intermediate 1C.2,2,2-Trifluoro-1-(4-(4,4,4-trifluorobutoxy)phenyl)ethanone: To asolution of Intermediate 1B (115 mmol) in anhydrous CH₂Cl₂ (320 mL) wasadded Dess-Martin periodinane (50.2 g, 118 mmol) portionwise at 0° C.The reaction was stirred at 0° C. for 0.5 h then at rt for 3 h. To thereaction was added 100 mL of sat'd aq. Na₂CO₃ and 250 mL of EtOAc. Thereaction was stirred for another 2 h. The insoluble material was removedby filtration. The layers were separated. The organic layer was washedwith sat'd aq. Na₂CO₃. Additional solids that formed upon standingovernight were removed. The organic solution was washed with sat'd aq.NaCl, dried over anhydrous MgSO₄, filtered and concentrated to provide adark brown liquid, which was purified by silica gel chromatography (220g silica gel, elute with EtOAc in hexanes to provide Intermediate 1C (26g, 76%) as a colorless oil.

Intermediate 1: To a solution of Intermediate 1C (10 g, 33.3 mmol) and(S)-2-methylpropane-2-sulfinamide (8.07 g, 66.6 mmol) in THF (125 mL)was added a solution of tetraisopropoxytitanium (37.9 g, 133 mmol) inTHF (45 mL) and the reaction mixture was stirred at 65° C. for 4 h. Thereaction solvent was removed under vacuum, the residue was dissolved inEtOAc (200 mL) and the solution was washed with sat. aq. NaHCO₃ (150mL). A large amount of solids formed that were filtered through CELITE®and washed with EtOAc (2×140 mL). The combined EtOAc solutions werewashed with sat. aq. NaHCO₃ (100 mL), dried over MgSO₄ and concentratedin vacuo to a yellow oil that purified by chromatography to give thedesired product as a yellow oil (9.64 g, 71.7%).

Intermediate 2(S,E)-2-Methyl-N-(2,2,2-trifluoro-1-(4-(6,6,6-trifluorohexyloxy)phenyl)ethylidene)propane-2-sulfinamide

Intermediate 2A. 4-(6,6,6-Trifluorohexyloxy)benzaldehyde: To asuspension of 4-hydroxybenzaldehyde (488 mg, 4 mmol) and6-bromo-1,1,1-trifluorohexane (657 mg, 3 mmol) in MeCN (10 mL) was addedK₂CO₃ (829 mg, 6.00 mmol). The resulting mixture was refluxed overnight.Insoluble material was filtered off and rinsed with MeCN. The combinedfiltrate was concentrated to afford a white solid. This white solid waspartitioned between EtOAc and 1 N NaOH solution. The organic layer wasseparated, washed with sat'd NH₄Cl, dried over MgSO₄, filtered andconcentrated to afford Intermediate 2A as a clear liquid. LCMS Anal.Calc'd for C₁₃H₁₅F₃O₂, 260.10. found [M+H] 261.0.

Intermediate 2B.2,2,2-Trifluoro-1-(4-(6,6,6-trifluorohexyloxy)phenyl)ethanone:Intermediate 2B was prepared using a procedure analogous to Intermediate1C except that Intermediate 1A was replaced with Intermediate 2A. ¹H NMR(500 MHz, CDCl₃) δ 8.06-8.02 (m, 2H), 6.99-6.97 (m, 1H), 4.08 (t, J=6.2Hz, 2H), 2.19-2.06 (m, 2H), 1.92-1.82 (m, 2H), 1.71-1.55 (m, 4H).

Intermediate 2: To a solution of Intermediate 2B (717 mg, 2.184 mmol)and (S)-2-methylpropane-2-sulfinamide (529 mg, 4.37 mmol) in THF (10 mL)was added tetraethoxytitanium (1993 mg, 8.74 mmol) in THF (20 mL). Theresulting mixture was reflux for 5 h. TLC (20% EtOAc in hexane)indicated the starting ketone was completely consumed. The solvent wasevaporated to afford a yellow oil. This yellow oil was dissolved inEtOAc and then washed with saturated NaHCO₃ (25 mL) and a large amountof white precipitation formed which was removed by filtering through abed of CELITE®. The white precipitate was rinsed with EtOAc. Thecombined EtOAc solution was washed again with saturated NaHCO₃, dried(MgSO₄) and concentrated. The crude product was purified by silica gelchromatography (40 g silica gel, eluted with EtOAc in hexanes) to affordIntermediate 2 (620 mg, 66%).

Intermediate 3(S,E)-2-Methyl-N-(2,2,2-trifluoro-1-(2-fluoro-4-((6,6,6-trifluorohexyl)oxy)phenyl)ethylidene)propane-2-sulfinamide

Intermediate 3 was prepared using a procedure analogous to Intermediate1 except that 4-hydroxybenzaldehyde was replaced with2-fluoro-4-hydroxybenzaldehyde. ¹H NMR (500 MHz, CDCl₃) δ 7.33-7.25 (m,1H), 6.80-6.62 (m, 2H), 4.05-3.93 (m, 2H), 2.22-2.02 (m, 2H), 1.91-1.76(m, 2H), 1.72-1.60 (m, 2H), 1.56 (s, 2H), 1.34 (s, 9H).

Intermediate 4(S,E)-2-Methyl-N-(2,2,2-trifluoro-1-(4-((5,5,5-trifluoropentyl)oxyphenyl)ethylidene)propane-2-sulfinamide

Intermediate 4 was prepared using a procedure analogous to Intermediate2 except that 6-bromo-1,1,1-trifluorohexane was replaced5-bromo-1,1,1-trifluoropentane in step 2A. ¹H NMR (500 MHz, CDCl₃) δ7.50 (d, J=8.5 Hz, 2H), 6.95 (d, J=9.1 Hz, 2H), 4.04 (t, J=5.9 Hz, 2H),2.31-2.10 (m, 2H), 1.94-1.85 (m, 2H), 1.84-1.70 (m, 2H).

Intermediate 5(S,E)-2-Methyl-N-(1,1,1-trifluorodec-3-yn-2-ylidene)propane-2-sulfinamide

Intermediate 5A 1,1,1-trifluorodec-3-yn-2-one: 2.5 M hexanes solution ofN-butyllithium (13.18 ml, 32.9 mmol) was added dropwise to a stirredsolution of oct-1-yne (3.3 g, 29.9 mmol) in THF (60 mL) at −50 to −60°C. The mixture was allowed to come to −5° C., cooled back to −60° C.followed by the addition of a solution ethyl 2,2,2-trifluoroacetate(4.68 g, 32.9 mmol) in THF (5 mL) at −60 to −55° C. The mixture wasallowed to RT and stirred at RT for 45 min. The reaction mixture wasquenched with saturated sodium bicarbonate solution and extracted withDCM. The organic phase was dried (MgSO₄) and concentrated at RT in vacuoto afford crude yellow oil 5A (6.1 g, 29.6 mmol, 99% yield). ¹H NMR (400MHz, CDCl₃) δ 2.50 (t, J=7.2 Hz, 2H), 1.70-1.62 (m, 2H), 1.48-1.39 (m,2H), 1.36-1.26 (m, 4H), 0.90 (t, J=6.9 Hz, 3H).

Intermediate 5 was prepared using a procedure analogous to Intermediate1 except that Intermediate 1C was replaced with Intermediate 5A. ¹H NMR(400 MHz, CDCl₃) δ 2.55 (t, J=7.2 Hz, 2H), 1.74-1.60 (m, 2H), 1.52-1.24(m, 15H), 0.93 (t, J=6.8 Hz, 3H).

Intermediate 6 1-(5-Cyclopropylthiophen-2-yl)ethanone

A reaction vial was charged with palladium acetate (6.99 mg, 0.031mmol), butyl di-1-adamantylphosphine (0.017 g, 0.047 mmol), potassiumcyclopropyl trifluoroborate (0.233 g, 1.572 mmol) and Cs₂CO₃ (1.521 g,4.67 mmol). The vessel was sealed, purged, and back-filled with argon. Asolution of 1-(5-chlorothiophen-2-yl)ethanone (0.250 g, 1.556 mmol) intoluene (5.7 mL) and water (0.57 mL) was added and the reaction mixturestirred at 100° C. for 16.5 h. The reaction mixture was cooled to rt,diluted with water and extracted with DCM (3×). The combined organiclayers were washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated. The crude product was purified by prep HPLC, affordedIntermediate 6 (39.2 mg, 0.236 mmol, 15.15% yield) as a yellow oil. ¹HNMR (500 MHz, CDCl₃) δ 7.53 (d, J=3.9 Hz, 1H), 6.79 (d, J=3.9 Hz, 1H),2.52 (s, 3H), 2.19-2.09 (m, 1H), 1.18-1.08 (m, 2H), 0.88-0.74 (m, 2H).LCMS Anal. Calc'd for C₉H₁₀OS, 166.0. found [M+H] 166.9.

Intermediate 7 1-(5-((Dimethylamino)methyl)thiophen-2-yl)ethanone

Intermediate 7A. 1-(5-(Hydroxymethyl)thiophen-2-yl)ethanone: To asolution of 5-acetylthiophene-2-carbaldehyde (0.800 g, 5.19 mmol) in THF(10.36 mL) was added sodium triacetoxyborohydride (1.210 g, 5.71 mmol)and the reaction mixture was stirred at 65° C. under argon for 6 h. Thereaction mixture was cooled to rt and quenched with sat. NH₄Cl. Theaqueous layer was separated and washed with DCM (3×). The combinedorganic layers were washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated. The crude product was purified bychromatography to yield Intermediate 7A (0.421 g, 2.70 mmol, 51.9%yield). LCMS Anal. Calc'd for C₇H₈O₂S, 156.0. found [M+H] 157.0. ¹H NMR(500 MHz, CDCl₃) δ 7.59 (d, J=3.9 Hz, 1H), 7.03 (d, J=3.6 Hz, 1H), 4.87(d, J=5.8 Hz, 2H), 2.55 (s, 3H), 2.03 (t, J=6.1 Hz, 1H).

Intermediate 7B. 1-(5-(Chloromethyl)thiophen-2-yl)ethanone:Methanesulfonyl chloride (0.419 mL, 5.38 mmol) was added dropwise to asolution of Intermediate 7A (420 mg, 2.69 mmol) and triethylamine (0.750mL, 5.38 mmol) in DCM (20.1 mL) and the reaction mixture was stirred atrt under argon for 2 d. The solvent was removed in vacuo and the crudeproduct was purified by chromatography to yield Intermediate 7B (488 mg,2.79 mmol, 104% yield). LCMS Anal. Calc'd for C₇H₇ClOS, 174.0. found[M+H] 175.1. ¹H NMR (500 MHz, CDCl₃) δ 7.55 (d, J=3.9 Hz, 1H), 7.15-7.07(m, 1H), 4.77 (d, J=0.6 Hz, 2H), 2.55 (s, 3H).

Intermediate 7: Dimethylamine (40 wt % in water) (0.181 mL, 1.431 mmol)was added to a solution of Intermediate 7B (50.00 mg, 0.286 mmol) inether (0.477 mL) and the reaction mixture stirred at rt for 18 h. Thereaction mixture was diluted with ether. The organic layer separated andextracted with 10% aq. citric acid. The aqueous layer was separated andtreated with 1N NaOH (to pH ˜10-11). The mixture was extracted withether (3×10 mL) and the combined organic layers were washed with brine,dried over anhydrous Na₂SO₄, filtered and concentrated. This materialwas purified by prep. HPLC to yield Intermediate 7 (35.3 mg, 0.119 mmol,41.5% yield) as a yellow oil. LCMS Anal. Calc'd for C₉H₁₃NOS, 183.1.found [M+H] 184.1. ¹H NMR (500 MHz, CDCl₃) δ 7.67 (d, J=3.9 Hz, 1H),7.34 (d, J=3.9 Hz, 1H), 4.44 (s, 2H), 2.86 (s, 6H), 2.59 (s, 3H).

Intermediate 8 1-(5-Methylthiazol-2-yl)ethanone

Intermediate 8: To a solution of 5-methylthiazole (0.179 mL, 2.017 mmol)in ether (13.63 mL) was added nBuLi (1.387 mL, 2.219 mmol, 1.6 M inhexanes) dropwise at −78° C. and the reaction mixture was stirred atthis temperature for 15 min. A solution of N-methoxy-N-methylacetamide(229 mg, 2.219 mmol) in THF (4.0 mL) was added dropwise and the reactionmixture warmed to rt and stirred for 1 h. The reaction mixture wasquenched with sat. NH₄Cl. The organic layer was separated and washedwith water, brine, dried over anhydrous Na₂SO₄, filtered andconcentrated. The crude product was purified by chromatography to yieldIntermediate 8 (123 mg, 0.871 mmol, 43.2% yield) as a pale yellow solid.¹H NMR (500 MHz, CDCl₃) δ 7.66 (s, 1H), 2.68 (s, 3H), 2.57 (s, 3H). LCMSAnal. Calc'd for C₆H₇NOS, 141.0. found [M+H] 141.9.

Intermediate 9 1-(6-(Dimethylamino)pyridin-3-yl)ethanone

Intermediate 9: A mixture of 1-(6-chloropyridin-3-yl)ethanone (0.100 g,0.643 mmol) and dimethylamine (40% in water) (0.407 mL, 3.21 mmol) inEtOH (1.071 mL) was stirred at 80° C. under argon for 2 h. The reactionmixture was cooled to rt. The EtOH was removed in vacuo and the residuewas dissolved in ether and washed with 10% citric acid. The aqueouslayer was separated and adjusted to pH=˜10-11 using 1N NaOH and thenextracted with ether (3×). The combined ether layers were washed withbrine, dried over anhydrous Na₂SO₄, filtered, concentrated and air driedunder vacuum to yield Intermediate 9 (98.1 mg, 0.597 mmol, 93% yield) asa crude light yellow solid which was used in the next step withoutfurther purification. ¹H NMR (500 MHz, CDCl₃) δ 8.78 (d, J=1.9 Hz, 1H),8.03 (dd, J=8.9, 2.3 Hz, 1H), 6.51 (d, J=9.1 Hz, 1H), 3.19 (s, 6H), 2.51(s, 3H). LCMS Anal. Calc'd for C₉H₁₂N₂O, 164.1. found [M+H] 165.1.

Intermediate 10 1-(1-Cyclopropyl-1H-pyrazol-4-yl)ethanone

Intermediate 10A. 1-Cyclopropyl-4-iodo-1H-pyrazole: To a mixture of4-iodo-1H-pyrazole (645 mg, 3.33 mmol), cyclopropylboronic acid (571 mg,6.65 mmol), copper(II) acetate (604 mg, 3.33 mmol) and DMAP (1219 mg,9.98 mmol) in dioxane (10 mL) was added pyridine (0.323 mL, 3.99 mmol).The resulting mixture was heated to 100° C. for 16 h under air. Thereaction mixture was concentrated in vacuo and diluted with EtOAc. Theorganic layer was washed with 1M HCl. The organic layer was dried overMgSO₄, filtered and concentrated in vacuo. The crude product waspurified by chromatography to give Intermediate 10A (660 mg, 2.82 mmol,85% yield) as a light yellow liquid. LCMS Anal. Calc'd for C₆H₇N₂,234.04. found [M+H] 234.9.

Intermediate 10: To a stirred solution of Intermediate 10A (460 mg,1.965 mmol) in THF (5 mL) at 0° C. was added iPrMgCl (1.081 mL, 2.162mmol) quickly. After 30 min, additional 0.15 eq of iPrMgCl was added andafter 30 min, the mixture was cooled to −78° C.N-Methoxy-N-methylacetamide (304 mg, 2.95 mmol) was added quickly andthe reaction was warmed to RT for 3 h. The reaction mixture wasconcentrated in vacuo and diluted with EtOAc. The organic layer waswashed with H₂O. The organic layer was dried over MgSO₄, filtered andconcentrated in vacuo. The crude product was purified to giveIntermediate 10 (250 mg, 1.665 mmol, 85% yield) as a clear liquid. LCMSAnal. Calc'd for C₈H₁₀N₂O, 150.8. found [M+H] 151.0.

Intermediate 11 1-(1-Cyclopropyl-1H-pyrazol-3-yl)ethanone

Intermediate 11: To a mixture of 1-(1H-pyrazol-3-yl)ethanone (160 mg,1.453 mmol), cyclopropylboronic acid (250 mg, 2.91 mmol), copper(II)acetate (264 mg, 1.453 mmol) and DMAP (533 mg, 4.36 mmol) in dioxane (10mL) was added pyridine (0.141 mL, 1.744 mmol). The resulting mixture washeated to 100° C. for 16 h under air. The reaction mixture wasconcentrated in vacuo and diluted with EtOAc. The organic layer waswashed with 1M HCl. The organic layer was dried over MgSO₄, filtered andconcentrated in vacuo. The crude product was purified by chromatographyto give Intermediate 11 (80 mg, 0.533 mmol, 36.7% yield) as a colorlessliquid. LCMS Anal. Calc'd for C₈H₁₀N₂O, 150.8. found [M+H] 151.1.

Intermediate 12 1-(1-(Cyclopropylmethyl)-1H-pyrazol-3-yl)ethanone

Intermediate 12: To a stirred solution of 1-(1H-pyrazol-3-yl)ethanone(300 mg, 2.72 mmol) and (bromomethyl)cyclopropane (405 mg, 3.00 mmol) inDMF (5 mL) was added K₂CO₃ (565 mg, 4.09 mmol). The reaction was heatedto 65° C. for 16 h. The reaction mixture was diluted with EtOAc andwater. The organic layer was washed with H₂O. The organic layer wasdried over MgSO₄, filtered and concentrated in vacuo. The crude productwas purified by chromatography to give Intermediate 12 (338 mg, 2.058mmol, 76% yield) as a clear liquid. LCMS Anal. Calc'd for C₉H₁₂N₂O,164.09. found [M+H] 165.1.

Intermediate 13 1-(1-Cyclobutyl-1H-pyrazol-3-yl)ethanone

Intermediate 13 was prepared using a procedure analogous to Intermediate12 except that (bromomethyl)cyclopropane was replaced bybromocyclobutane. LCMS Anal. Calc'd for C₉H₁₂N₂O, 164.09. found [M+H]165.1.

Intermediate 14 1-(1-(Cyclobutylmethyl)-1H-pyrazol-3-yl)ethanone

Intermediate 14 was prepared using a procedure analogous to Intermediate12 except that (bromomethyl)cyclopropane was replaced by(bromomethyl)cyclobutane. LCMS Anal. Calc'd for C₁₀H₁₄N₂O, 178.11. found[M+H] 179.1.

Intermediate 15 1-(1-Isopropyl-1H-pyrazol-3-yl)ethanone

Intermediate 15 was prepared using a procedure analogous to Intermediate12 except that (bromomethyl)cyclopropane was replaced by 2-iodopropane.LCMS Anal. Calc'd for C₁₀H₁₄N₂O, 152.10. found [M+H] 153.1.

Intermediate 16 1-(1-(tert-Butyl)-1H-pyrazol-3-yl)ethanone

Intermediate 16: To a stirred solution of 1-(1H-pyrazol-3-yl)ethanone(100 mg, 0.908 mmol) and 2-methylpropan-2-ol (337 mg, 4.54 mmol) washeated to 30° C. H₂SO₄ (48.4 μl, 0.908 mmol) was added dropwise and thereaction was heated to 100° C. for 4 h.

The reaction was cooled to RT and diluted with EtOAc. The organic layerwas washed with sat. NaHCO₃. The organic layer was dried over MgSO₄,filtered and concentrated in vacuo. The crude product was purified bychromatography to give Intermediate 16 (20 mg, 0.120 mmol, 13.25% yield)as a clear liquid. ¹H NMR (500 MHz, CDCl₃) δ 7.52 (d, J=2.5 Hz, 1H),6.76 (d, J=2.5 Hz, 1H), 2.58 (s, 3H), 1.62 (s, 9H).

Intermediate 17(S,E)-2-Methyl-N-(2,2,2-trifluoro-1-(4-(5,5,5-trifluoropentyl)phenyl)ethylidene)propane-2-sulfinamide

Intermediate 17 was prepared using a procedure similar toIntermediate 1. ¹H NMR (500 MHz, CDCl₃) δ 7.40 (d, J=8.0 Hz, 2H),7.30-7.20 (m, 2H), 2.76-2.59 (m, 2H), 2.17-2.00 (m, 2H), 1.80-1.67 (m,2H), 1.66-1.58 (m, 2H), 1.31 (s, 9H).

Intermediate 18(S,E)-N-(1-(2-Chloro-4-(4,4,4-trifluorobutoxy)phenyl)-2,2,2-trifluoroethylidene)-2-methylpropane-2-sulfinamide

Intermediate 18 was prepared using a procedure similar toIntermediate 1. ¹H NMR (500 MHz, CDCl₃) δ 7.17 (d, J=8.5 Hz, 1H), 6.89(d, J=2.5 Hz, 1H), 6.78-6.72 (m, 1H), 3.95 (br. s., 2H), 2.31-2.16 (m,2H), 1.99 (d, J=9.6 Hz, 2H), 1.24 (s, 9H). LCMS Anal. Calc'd forC₁₆H₁₈ClF₆NO₂S, 437.1. found [M+H] 438.1.

Intermediate 19(S,E)-2-Methyl-N-(2,2,2-trifluoro-1-(2-methoxy-4-(4,4,4-trifluorobutoxy)phenyl)ethylidene)propane-2-sulfinamide

Intermediate 19 was prepared using a procedure similar toIntermediate 1. ¹H NMR (500 MHz, CDCl₃) δ 7.28-7.22 (m, 1H), 6.53-6.50(m, 1H), 6.49 (s, 1H), 4.06 (s, 2H), 3.92 (s, 3H), 2.40-2.28 (m, 2H),2.13-2.02 (m, 2H), 1.31 (s, 9H). LCMS Anal. Calc'd for C₁₇H₂₁F₆NO₃S,433.1. found [M+H] 434.1.

Intermediate 20 1-(1-Ethyl-1H-pyrazol-3-yl)ethanone

Intermediate 20 was prepared using a procedure analogous to Intermediate12 except that (bromomethyl)cyclopropane was replaced by iodoethane. ¹HNMR (500 MHz, CDCl₃) δ 7.43 (d, J=2.48 Hz, 1H), 6.77 (d, J=2.48 Hz, 1H),4.24 (q, J=7.43 Hz, 2H), 2.57 (s, 3H), 1.53 (t, J=7.43 Hz, 3H). LCMSAnal. Calc'd for C₇H₁₀N₂O, 138.08. found [M+H] 139.1.

Intermediate 21 1-(1-Isobutyl-1H-pyrazol-3-yl)ethanone

Intermediate 21 was prepared using a procedure analogous to Intermediate12 except that (bromomethyl)cyclopropane was replaced by1-bromo-2-methylpropane. ¹H NMR (500 MHz, CDCl₃) δ 7.34 (d, J=2.48 Hz,1H), 6.72 (d, J=2.48 Hz, 1H), 3.93 (d, J=7.43 Hz, 2H), 2.52 (s, 3H),2.20 (sept, J=7.15 Hz, 1H), 0.88 (d, J=6.60 Hz, 6H). LCMS Anal. Calc'dfor C₉H₁₄N₂O, 166.11. found [M+H] 167.1.

Intermediate 22 1-(5-Cyclopropylthiazol-2-yl)ethanone

Intermediate 22A. 5-Cyclopropyl-2-(1,1-dimethoxyethyl)thiazole: To adegassed solution of 5-bromo-2-(1,1-dimethoxyethyl)thiazole (0.500 g,1.983 mmol), prepared using the procedure described in WO 2004/087699,and [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium (II)complex with dichloromethane (1:1) (0.162 g, 0.198 mmol) in THF (19.83mL) was added cyclopropylzinc(II) bromide, 0.5 M in THF (19.83 mL, 9.92mmol) and the reaction mixture was degassed an additional 3 times. Thereaction mixture was then heated at 65° C. for 20 h, cooled to rt,diluted with water and extracted with EtOAc (3×). The combined organicphases were washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by flash chromatography (silicagel, hexanes:EtOAc, 100:0 to 70:30) to afford 0.327 g (77%) ofIntermediate 22A as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.48 (d,J=0.8 Hz, 1H), 3.25 (s, 6H), 2.10-1.96 (m, 1H), 1.70 (s, 3H), 1.09-0.96(m, 2H), 0.78-0.66 (m, 2H). LCMS Anal. Calc'd for C₁₀H₁₅NO₂S, 213.0.found [M+H−MeOH] 182.0.

Intermediate 22: To a solution of Intermediate 22A (327 mg, 1.533 mmol)in DCM (1.821 mL) was added TFA (1.181 mL, 15.33 mmol) and Water (0.091mL) and the reaction mixture stirred at RT for 2 h. The solvent wasremoved in vacuo and the residue was dissolved in DCM, washed with sat.NaHCO₃, water and brine. The organic phase was dried over anhydrousNa₂SO₄, filtered and concentrated. The residue was purified by flashchromatography (silica gel, hexanes:EtOAc, 100:0 to 0:100) to afford0.189 g (74%) of Intermediate 22 as a yellow oil. ¹H NMR (500 MHz,CDCl₃) δ 7.70 (s, 1H), 2.66 (s, 3H), 2.24-2.06 (m, 1H), 1.24-1.13 (m,2H), 0.93-0.80 (m, 2H). LCMS Anal. Calc'd for C₈H₉NOS, 167.0. found[M+H] 167.9.

Intermediate 23 1-(5-Ethylthiazol-2-yl)ethanone

Intermediate 23A. 1-(5-Bromothiazol-2-yl)ethanone: To a solution of5-bromo-2-(1,1-dimethoxyethyl)thiazole (0.828 g, 3.28 mmol) in DCM (3.90mL) was added TFA (2.53 mL, 32.8 mmol) and water (0.195 mL) and thereaction mixture stirred at 23° C. under Ar at 1 atm for 2 h. Thesolvent was removed in vacuo (azeotroped with MeOH, 2×) and the residuewas dissolved in DCM, washed with sat. NaHCO₃, water and brine. Theorganic layer was dried over anhydrous Na₂SO₄, filtered, concentratedand air-dried under vacuum to give a crude product. The crude productwas further purified by ISCO (Hex:EtOAc 0-20%) to give Intermediate 23A(640 mg, 3.11 mmol, 95% yield) as a crude light brown solid. LCMS Anal.Calc'd for C₅H₄BrNOS, 204.9. found [M+H] 206.1.

Intermediate 23B. 1-(5-Vinylthiazol-2-yl)ethanone: A solution ofpotassium vinyltrifluoroborate (0.332 g, 2.475 mmol), palladium (II)chloride (8.78 mg, 0.050 mmol), Ph₃P (0.039 g, 0.149 mmol), Cs₂CO₃(0.806 g, 2.475 mmol) and Intermediate 23A (0.510 g, 2.475 mmol) in amixture of THF (4.2 ml) and water (0.467 ml) was heated in a sealedreaction vial at 85° C. for 16 h. The reaction mixture was cooled to rtand diluted with water followed by extraction with DCM (3×). Thecombined organic extracts were dried over anhydrous Na₂SO₄, filtered andconcentrated. The crude product was dissolved in a small amount ofdichloromethane and charged to a 40 g silica gel cartridge which waseluted with a gradient from 0 to 30% hexane/ethyl acetate. The desiredfractions were concentrated and air-dried under vacuum to yieldIntermediate 23B (0.250 g, 1.632 mmol, 65.9% yield) as a yellow oil. ¹HNMR (400 MHz, Chloroform-d) δ 7.81 (s, 1H), 6.83 (dd, J=17.3, 10.9 Hz,1H), 5.78 (d, J=17.4 Hz, 1H), 5.46 (d, J=11.0 Hz, 1H), 2.68 (s, 3H).LCMS Anal. Calc'd for C₇H₇NOS, 153.02. found [M+H] 154.3.

Intermediate 23: A mixture of Intermediate 23B (431 mg, 2.81 mmol) Pd/C(58 mg, 0.055 mmol, ˜10% wt) in MeOH (30 mL) was hydrogenated at 1 atmfor 18 min. Catalyst was filtered off through CELITE®. The filtrate wasconcentrated to give the crude product which was charged to a 24 gsilica gel cartridge which was eluted with a gradient from 0 to 30%hexane/ethyl acetate. Desired fractions were collected and concentratedusing a rotary evaporator to give Intermediate 23 as colorless oil (395mg, 90%). ¹H NMR (400 MHz, Chloroform-d) δ 7.68 (t, J=1.0 Hz, 1H), 2.93(qd, J=7.5, 1.0 Hz, 2H), 2.67 (s, 3H), 1.36 (t, J=7.5 Hz, 3H). LCMSAnal. Calc'd for C₇H₉NOS, 155.04. found [M+H] 156.3.

Example 1(S)-4-(5-Cyclopropylthiophen-2-yl)-3-(1H-tetrazol-5-yl)-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-5,6-dihydropyridin-2(1H)-one

1A.(S)—N—((S)-4-(5-Cyclopropylthiophen-2-yl)-1,1,1-trifluoro-4-oxo-2-(4-(4,4,4-trifluorobutoxy)phenyl)butan-2-yl)-2-methylpropane-2-sulfinamide:To a solution of Intermediate 5 (37.1 mg, 0.223 mmol) in THF (1.195 mL)at −78° C. was added KHMDS (1.0 M in THF) (0.223 mL, 0.223 mmol). Theresulting mixture was stirred at −78° C. for 20 min and Intermediate 1(60 mg, 0.149 mmol) in THF (0.598 mL), was added. Stirring was continuedat −78° C. for an additional 1 h. The reaction mixture was quenched withsat. aq. NH₄Cl and was diluted with EtOAc (5 mL) and water (5 mL). Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated. Purification by chromatography to yield 1A(41.5 mg, 0.073 mmol, 49.0% yield) as a clear oil. ¹H NMR (500 MHz,CDCl₃) δ 7.59 (d, J=8.8 Hz, 2H), 7.54 (d, J=3.9 Hz, 1H), 6.92 (d, J=8.8Hz, 2H), 6.80 (d, J=3.9 Hz, 1H), 6.67 (s, 1H), 4.04 (t, J=5.9 Hz, 2H),3.79 (d, J=16.2 Hz, 1H), 3.61 (d, J=16.2 Hz, 1H), 2.42-2.26 (m, 2H),2.19-2.11 (m, 1H), 2.10-2.00 (m, 2H), 1.30 (s, 9H), 1.19-1.10 (m, 2H),0.86-0.78 (m, 2H). LCMS Anal. Calc'd for C₂₅H₂₉F₆NO₃S₂, 569.1. found[M+H] 570.0.

1B.(S)-3-Amino-1-(5-cyclopropylthiophen-2-yl)-4,4,4-trifluoro-3-(4-(4,4,4-trifluorobutoxy)phenyl)butan-1-one:To a solution of 1A (40.0 mg, 0.070 mmol) in MeOH (0.351 mL) was addedHCl (4 M in dioxane) (0.083 mL, 0.330 mmol) and the reaction mixturestirred under argon for 1 h. The solvent was removed in vacuo and theresidue was dissolved in EtOAc, washed with sat. NaHCO₃ and brine. Theorganic layer was dried over anhydrous Na₂SO₄, filtered, concentrated toyield 1B (29.4 mg, 0.063 mmol, 90% yield) as a crude light yellow oilwhich was used in the next step without further purification. LCMS Anal.Calc'd for C₂₁H₂₁F₆NO₂S, 465.12. found [M+H] 466.0.

1C.(S—N-(4-(5-Cyclopropylthiophen-2-yl)-1,1,1-trifluoro-4-oxo-2-(4-(4,4,4-trifluorobutoxy)phenyl)butan-2-yl)-2-(1H-tetrazol-5-yl)acetamide:To a solution of 1B (29.4 mg, 0.063 mmol) andN,N′-methanediylidenedicyclohexanamine (39.1 mg, 0.189 mmol) in THF(0.545) mL) was added a solution of (1H-tetrazol-5-yl)-acetic acid(24.27 mg, 0.189 mmol) in THF (0.545 mL) and the reaction mixturestirred at rt under argon, 1 atm for 2 h. The solids formed werefiltered and the residue was purified by chromatography to yield 1C(32.1 mg, 0.056 mmol, 88% yield) as a white solid. LCMS Anal. Calc'd forC₂₄H₂₃F₆N₅O₃S, 576.50. found [M+H] 577.0.

Example 1

To a solution of 1C (30.1 mg, 0.052 mmol) in EtOH (1.090 mL) was addedpiperidine (7.25 μL, 0.073 mmol) and the reaction mixture stirred at 80°C. in a sealed vial for 24 h. The solvent was removed in vacuo. Theresidue was purified by prep HPLC to yield Example 1 (19.7 mg, 0.056mmol, 66% yield). LCMS Anal. Calc'd for C₂₄H₂₁F₆N₅O₂S, 558.13. found[M+H] 559.0. ¹H NMR (500 MHz, DMSO-d₆) δ 9.49 (br. s., 1H), 7.69-7.57(m, 3H), 7.01 (d, J=8.5 Hz, 2H), 6.79 (d, J=3.9 Hz, 1H), 4.06 (t, J=6.1Hz, 2H), 3.92 (d, J=17.3 Hz, 1H), 3.59 (d, J=17.3 Hz, 1H), 2.47-2.33 (m,2H), 2.03-1.97 (m, 1H), 1.97-1.89 (m, 2H), 1.05-0.90 (m, 2H), 0.66-0.51(m, 2H).

The following Examples in Table 2 were prepared in a similar manner asExample 1 utilizing sulfinamide (Intermediates 1-5 and 17-19) andheterocyclic ketone (Intermediates 6-16 and 20-13, or commerciallyavailable ketones) as starting materials.

TABLE 2 Example No. Structure and Name Analytical Data  2

¹H NMR (500 MHz, 1:1 MeOD:CDCl₃) δ 7.51 (d, J = 8.8 Hz, 2H), 7.05 (d, J= 3.9 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.67 (dd, J = 3.9, 0.8 Hz, 1H),4.02 (t, J = 5.9 Hz, 2H), 3.79-3.70 (m, 1H), 3.67-3.58 (m, 1H), 2.34 (s,3H), 2.33-2.25 (m, 2H), 2.07-1.97 (m, 2H). MS (ESI) m/z: 532.2 (M + H)⁺. 3

¹H NMR (500 MHz, MeOD) δ 7.59 (d, J = 8.8 Hz, 2H), 7.42 (d, J = 4.4 Hz,1H), 7.04-6.97 (m, 3H), 4.07 (t, J = 6.2 Hz, 2H), 3.91 (d, J = 17.1 Hz,1H), 3.70 (d, J = 17.3 Hz, 1H), 2.43-2.30 (m, 2H), 2.08-1.96 (m, 2H). MS(ESI) m/z: 552.0 (M + H)⁺.  4

¹H NMR (500 MHz, DMSO) δ 9.43 (br. s., 1H), 7.63 (d, J = 8.0 Hz, 2H),7.57 (br. s., 1H), 7.00 (d, J = 8.0 Hz, 2H), 6.78 (br. s., 1H), 4.01(br. s., 2H), 3.91 (d, J = 16.8 Hz, 1H), 3.59 (d, J = 17.3 Hz, 1H),2.36-2.18 (m, 2H), 1.99 (d, J = 3.9 Hz, 1H), 1.75 (br. s., 2H),1.57-1.44 (m, 4H), 0.98 (d, J = 7.2 Hz, 2H), 0.58 (br. s., 2H). MS (ESI)m/z: 604.1 (M + H)⁺.  5

¹H NMR (500 MHz, 1:1 MeOD:CDCl₃) δ 7.10 (d, J = 4.5 Hz, 1H), 6.87 (d, J= 4.0 Hz, 1H), 3.47 (d, J = 5.0 Hz, 2H), 2.27 (t, J = 7.2 Hz, 2H),1.59-1.48 (m, 2H), 1.45-1.35 (m, 2H), 1.32- 1.20 (m, 4H), 0.88 (t, J =6.9 Hz, 3H). MS (ESI) m/z: 458.0 (M + H)⁺.  6

¹H NMR (400 MHz, CDCl₃) δ 7.05-6.97 (m, 2H), 6.91 (s, 1H), 3.56-3.35 (m,2H), 2.22 (t, J = 7.2 Hz, 2H), 1.50 (quin, J = 7.3 Hz, 2H), 1.40-1.14(m, 6H), 0.86 (t, J = 6.8 Hz, 3H). MS (ESI) m/z: 504.2 (M + H)⁺.  7

¹H NMR (500 MHz, DMSO-d₆) δ 9.68 (br. s., 1H), 8.25 (br. s., 1H), 7.89(d, J = 6.3 Hz, 1H), 7.82 (d, J = 6.1 Hz, 1H), 7.69 (d, J = 8.0 Hz, 2H),7.40 (d, J = 3.9 Hz, 2H), 7.03 (d, J = 8.0 Hz, 2H), 4.16- 3.99 (m, 3H),3.81 (d, J = 7.6 Hz, 1H), 2.45-2.31 (m, 2H), 1.93 (br. s., 2H). MS (ESI)m/z: 568.1 (M + H)⁺.  8

¹H NMR (500 MHz, 1:1 MeOD:CDCl₃) δ 7.46 (t, J = 9.4 Hz, 1H), 7.07 (d, J= 3.5 Hz, 1H), 6.77 (dd, J = 8.9, 2.5 Hz, 1H), 6.71-6.56 (m, 2H), 4.14(d, J = 16.8 Hz, 1H), 3.98 (t, J = 6.2 Hz, 2H), 3.58 (d, J = 16.8 Hz,1H), 2.23-2.05 (m, 2H), 1.98-1.90 (m, 1H), 1.85-1.74 (m, 2H), 1.66- 1.49(m, 4H), 1.02-0.91 (m, 2H), 0.65-0.51 (m, 2H). MS (ESI) m/z: 587.0 (M +H)⁺.  9

¹H NMR (400 MHz, CDCl₃) δ 7.45 (d, J = 8.8 Hz, 2H), 7.20 (d, J = 3.7 Hz,1H), 7.12 (br. s., 1H), 6.94 (d, J = 8.8 Hz, 2H), 6.79 (d, J = 4.0 Hz,1H), 4.03 (t, J = 5.9 Hz, 2H), 3.75, 3.68 (ABq, J = 17.4 Hz, 2H), 2.85(q, J = 7.5 Hz, 2H), 2.41-2.25 (m, 2H), 2.08 (dt, J = 15.7, 6.0 Hz, 2H),1.31 (t, J = 7.5 Hz, 3H). MS (ESI) m/z: 546.3 (M + H)⁺. 10

¹H NMR (500 MHz, DMSO-d₆) δ 9.54 (br. s., 1H), 7.58 (d, J = 7.7 Hz, 2H),7.46 (br. s., 1H), 7.02 (d, J = 6.9 Hz, 2H), 6.73 (br. s., 1H), 4.07(br. s., 2H), 3.65 (d, J = 17.3 Hz, 1H), 3.52 (br. s., 1H), 2.42 (d, J =3.6 Hz, 2H), 1.93 (br. s., 2H), 1.63 (br. s., 3H). MS (ESI) m/z: 532.1(M + H)⁺. 11

¹H NMR (500 MHz, CDCl₃) δ 9.36 (br. s., 1H), 7.64 (d, J = 7.7 Hz, 2H),7.49 (br. s., 1H), 7.22 (br. s., 1H), 7.01 (d, J = 7.7 Hz, 2H), 4.06(br. s., 2H), 3.87 (d, J = 16.8 Hz, 1H), 3.59 (d, J = 17.3 Hz, 1H),2.47-2.31 (m, 2H), 2.14 (br. s., 3H), 1.93 (br. s., 2H). MS (ESI) m/z:532.1 (M + H)⁺. 12

¹H NMR (500 MHz, DMSO-d₆) δ 9.66 (s, 1H), 7.83 (d, J = 3.9 Hz, 1H), 7.66(d, J = 8.8 Hz, 2H), 7.27 (d, J = 3.9 Hz, 1H), 7.03 (d, J = 9.1 Hz, 2H),4.36 (s, 2H), 4.07 (t, J = 6.1 Hz, 2H), 3.97 (d, J = 17.6 Hz, 1H), 3.71(d, J = 17.6 Hz, 1H), 3.25-3.19 (m, 2H), 2.63 (s, 6H), 2.47-2.35 (m,2H). MS (ESI) m/z: 575.2 (M + H)⁺. 13

¹H NMR (500 MHz, DMSO-d₆) δ 9.83 (br. s., 1H), 7.76 (s, 1H), 7.55 (d, J= 8.8 Hz, 2H), 7.03 (d, J = 8.8 Hz, 2H), 4.21 (d, J = 17.6 Hz, 1H), 4.05(t, J = 6.1 Hz, 2H), 3.73 (d, J = 17.6 Hz, 1H), 2.46- 2.33 (m, 5H),1.98-1.82 (m, 2H). MS (ESI) m/z: 533.1 (M + H)⁺. 14

¹H NMR (500 MHz, DMSO-d₆) δ 9.54 (s, 1H), 7.78 (d, J = 2.5 Hz, 1H), 7.64(d, J = 8.8 Hz, 2H), 7.14 (dd, J = 9.1, 2.2 Hz, 1H), 7.01 (d, J = 8.8Hz, 2H), 6.62 (d, J = 8.8 Hz, 1H), 4.07 (t, J = 6.2 Hz, 2H), 3.80-3.62(m, 2H), 3.04 (s, 6H), 2.47-2.30 (m, 2H), 1.99- 1.85 (m, 2H). MS (ESI)m/z: 556.1 (M + H)⁺. 15

¹H NMR (500 MHz, DMSO-d₆) δ 9.40 (br. s., 1H), 7.91 (br. s., 1H), 7.55(t, J = 9.5 Hz, 1H), 6.91 (dd, J = 7.3, 2.1 Hz, 1H), 4.02 (t, J = 6.3Hz, 2H), 3.95 (d, J = 17.3 Hz, 1H), 3.75-3.66 (m, 1H), 3.50 (d, J = 17.3Hz, 1H), 2.34-2.20 (m, 2H), 1.74 (quin, J = 6.9 Hz, 2H), 1.60-1.43 (m,4H), 1.04-0.91 (m, 4H). MS (ESI) m/z: 588.2 (M + H)⁺. 16

¹H NMR (500 MHz, MeOD) δ 7.60 (d, J = 2.5 Hz, 1H), 7.54 (t, J = 9.2 Hz,1H), 6.83 (dd, J = 8.8, 2.5 Hz, 1H), 6.77 (dd, J = 14.9, 2.5 Hz, 1H),5.66 (d, J = 2.5 Hz, 1H), 4.40-4.33 (m, 1H), 4.05- 4.01 (m, 2H),3.71-3.65 (m, 1H), 3.64-3.57 (m, 1H), 2.26-2.14 (m, 2H), 1.87-1.79 (m,2H), 1.71- 1.54 (m, 4H), 1.01-0.94 (m, 4H). MS (ESI) m/z: 588.2 (M +H)⁺. 17

¹H NMR (400 MHz, MeOD) δ 7.58 (d, J = 8.8 Hz, 3H), 7.07- 6.91 (m, 2H),5.60 (d, J = 2.2 Hz, 1H), 4.15-4.01 (m, 3H), 3.73- 3.55 (m, 2H),2.43-2.23 (m, 2H), 2.08-1.93 (m, 2H), 1.00-0.90 (m, 4H). MS (ESI) m/z:542.2 (M + H)⁺. 18

¹H NMR (500 MHz, DMSO-d₆) δ 9.43 (br. s., 1H), 8.11 (s, 1H), 7.67 (d, J= 8.3 Hz, 2H), 7.03 (d, J = 8.0 Hz, 2H), 6.50 (s, 1H), 4.08 (t, J = 5.9Hz, 2H), 3.80 (d, J = 17.6 Hz, 1H), 3.73-3.66 (m, 1H), 3.55 (d, J = 17.6Hz, 1H), 2.01- 1.85 (m, 2H), 1.80-1.46 (m, 4H), 1.36-1.03 (m, 2H). MS(ESI) m/z: 542.2 (M + H)⁺. 19

¹H NMR (500 MHz, DMSO-d₆) δ 9.47 (br. s., 1H), 7.68 (br. s., 1H), 7.60(d, J = 8.0 Hz, 2H), 7.03 (d, J = 8.3 Hz, 3H), 5.25 (br. s, 1H),4.17-4.03 (m, 2H), 3.95 (t, J = 8.7 Hz, 2H), 3.54 (d, J = 17.3 Hz, 1H),2.49-2.34 (m, 2H), 2.03- 1.87 (m, 2H), 1.16 (d, J = 6.3 Hz, 1H), 0.51(d, J = 7.7 Hz, 2H), 0.33 (br. s., 2H). MS (ESI) m/z: 556.1 (M + H)⁺. 20

¹H NMR (500 MHz, DMSO-d₆) δ 9.54 (br. s., 1H), 7.76 (br. s., 1H), 7.62(d, J = 8.3 Hz, 2H), 7.04 (d, J = 8.0 Hz, 2H), 5.65 (br. s., 1H), 4.87(quin, J = 8.3 Hz, 1H), 4.13- 3.97 (m, 3H), 3.58 (d, J = 17.9 Hz, 1H),2.48-2.37 (m, 2H), 2.35- 2.20 (m, 4H), 1.99-1.88 (m, 2H), 1.82-1.67 (m,2H). MS (ESI) m/z: 556.1 (M + H)⁺. 21

¹H NMR (500 MHz, DMSO-d₆) δ 9.54 (br. s., 1H), 7.65 (br. s., 1H), 7.59(d, J = 8.3 Hz, 2H), 7.03 (d, J = 8.3 Hz, 2H), 5.34 (br. s., 1H),4.18-4.00 (m, 5H), 3.55 (d, J = 17.6 Hz, 1H), 2.65 (t, J = 7.4 Hz, 1H),2.43 (dd, J = 17.5, 10.0 Hz, 2H), 2.01-1.66 (m, 8H). MS (ESI) m/z: 570.2(M + H)⁺. 22

¹H NMR (500 MHz, MeOD) δ 7.69-7.48 (m, 3H), 7.28 (d, J = 8.5 Hz, 2H),5.50 (d, J = 2.2 Hz, 1H), 4.18 (d, J = 17.9 Hz, 1H), 4.04-3.83 (m, 2H),3.65 (d, J = 17.6 Hz, 1H), 2.66 (t, J = 7.7 Hz, 2H), 2.25-2.07 (m, 2H),1.71 (t, J = 7.8 Hz, 2H), 1.63-1.49 (m, 2H), 1.19 (s, 1H), 0.64-0.51 (m,2H), 0.37-0.28 (m, 2H). MS (ESI) m/z: 554.3 (M + H)⁺. 23

¹H NMR (500 MHz, MeOD) δ 7.65-7.47 (m, 3H), 7.28 (d, J = 8.5 Hz, 2H),5.67 (d, J = 2.5 Hz, 1H), 4.43 (dt, J = 13.4, 6.6 Hz, 1H), 4.19-4.06 (m,1H), 3.71- 3.59 (m, 1H), 2.66 (t, J = 7.7 Hz, 2H), 2.24-2.08 (m, 2H),1.78- 1.66 (m, 2H), 1.63-1.51 (m, 2H), 1.36 (dd, J = 6.6, 5.0 Hz, 6H).MS (ESI) m/z: 542.3 (M + H)⁺. 24

¹H NMR (500 MHz, MeOD) δ 6.06-5.90 (m, 3H), 5.70 (d, J = 8.3 Hz, 2H),4.01 (d, J = 2.2 Hz, 1H), 2.51 (d, J = 17.9 Hz, 1H), 2.13-2.01 (m, 2H),1.12-1.04 (m, 2H), 0.66-0.48 (m, 2H), 0.17- 0.07 (m, 2H), 0.04-0.06 (m,2H). MS (ESI) m/z: 540.3 (M + H)⁺. 25

¹H NMR (500 MHz, MeOD) δ 7.62-7.49 (m, 3H), 6.96 (d, J = 9.1 Hz, 2H),5.58 (d, J = 2.2 Hz, 1H), 4.09 (d, J = 17.6 Hz, 1H), 4.00 (t, J = 6.3Hz, 2H), 3.69- 3.63 (m, 1H), 3.62-3.56 (m, 1H), 2.27-2.08 (m, 2H),1.90-1.75 (m, 2H), 1.69-1.48 (m, 4H), 1.01- 0.91 (m, 4H). MS (ESI) m/z:570.3 (M + H)⁺. 26

¹H NMR (500 MHz, MeOD) δ 7.61-7.48 (m, 3H), 7.00-6.92 (m, 2H), 5.67 (d,J = 2.5 Hz, 1H), 4.49-4.35 (m, 1H), 4.12 (d, J = 17.6 Hz, 1H), 4.05-3.94(m, 2H), 3.61 (d, J = 17.6 Hz, 1H), 2.25- 2.08 (m, 2H), 1.83-1.75 (m,2H), 1.68-1.51 (m, 4H), 1.36 (dd, J = 6.6, 5.0 Hz, 6H). MS (ESI) m/z:572.3 (M + H)⁺. 27

¹H NMR (500 MHz, MeOD) δ 7.63 (d, J = 2.8 Hz, 1H), 7.58 (d, J = 8.8 Hz,2H), 6.99-6.90 (m, 2H), 5.90 (d, J = 2.8 Hz, 1H), 4.10 (d, J = 17.6 Hz,1H), 4.00 (td, J = 6.3, 1.1 Hz, 2H), 3.61 (d, J = 17.6 Hz, 1H),2.27-2.08 (m, 2H), 1.85-1.74 (m, 2H), 1.67- 1.51 (m, 4H), 1.42 (s, 9H).MS (ESI) m/z: 586.3 (M + H)⁺. 28

¹H NMR (500 MHz, DMSO-d₆) δ 9.43 (br. s., 1H), 8.04 (br. s., 1H), 7.59(d, J = 8.3 Hz, 2H), 7.00 (d, J = 8.3 Hz, 2H), 6.79 (d, J = 9.1 Hz, 1H),6.58 (d, J = 8.8 Hz, 1H), 4.14-3.98 (m, 3H), 3.49 (br. s., 1H), 2.93 (s,6H), 2.41 (dd, J = 16.9, 10.6 Hz, 2H), 1.99-1.84 (m, 2H). MS (ESI) m/z:556.3 (M + H)⁺. 29

¹H NMR (500 MHz, CD₃OD) δ 7.57 (d, J = 8.80 Hz, 2H), 7.49 (d, J = 2.48Hz, 1H), 6.95 (d, J = 9.08 Hz, 2H), 5.48 (d, J = 2.48 Hz, 1H), 4.16 (d,J = 17.33 Hz, 1H), 4.12 (q, J = 7.43 Hz, 2H), 4.00 (t, J = 6.33 Hz, 2H),3.62 (d, J = 17.61 Hz, 1H), 2.12-2.22 (m, 2H), 1.77-1.83 (m, 2H),1.53-1.66 (m, 4H), 1.36 (t, J = 7.15, 9H). MS (ESI) m/z: 558.2 (M + H)⁺.30

¹H NMR (500 MHz, CD₃OD) δ 7.57 (d, J = 8.80 Hz, 2H), 7.55 (d, J = 2.48Hz, 1H), 6.96 (d, J = 8.80 Hz, 2H), 5.50 (d, J = 2.48 Hz, 1H), 4.17 (d,J = 17.61 Hz, 1H), 4.00 (t, J = 6.33 Hz, 2H), 3.89-3.98 (m, 2H), 3.61(d, J = 17.61 Hz, 1H), 2.12-2.22 (m, 2H), 1.77-1.83 (m, 2H), 1.55- 1.66(m, 4H), 1.16-1.22 (m, 1H), 0.54-0.58 (m, 2H), 0.31- 0.34 (m, 2H). MS(ESI) m/z: 584.3 (M + H)⁺. 31

¹H NMR (500 MHz, CD₃OD) δ 7.56 (d, J = 8.80 Hz, 2H), 7.47 (d, J = 2.48Hz, 1H), 6.95 (d, J = 9.08 Hz, 2H), 5.51 (d, J = 2.20 Hz, 1H), 4.17 (d,J = 17.61 Hz, 1H), 4.00 (t, J = 6.33 Hz, 2H), 3.85-3.92 (m, 2H), 3.60(d, J = 17.61 Hz, 1H), 2.12-2.22 (m, 2H), 2.04-2.09 (m, 1H), 1.77- 1.83(m, 2H), 1.53-1.66 (m, 4H), 0.84 (t, J = 6.60 Hz, 6H). MS (ESI) m/z:586.3 (M + H)⁺. 32

¹H NMR (500 MHz, CD₃OD) δ 7.58 (d, J = 8.53 Hz, 2H), 7.06 (s, 1H), 6.95(d, J = 9.08 Hz, 2H), 6.68 (t, J = 2.75 Hz, 1H), 5.15 (s, 1H), 4.21(sept, J = 6.60 Hz, 1H), 4.00 (t, J = 6.33 Hz, 2H), 3.80 (d, J = 17.06Hz, 1H), 3.57 (d, J = 17.33 Hz, 1H), 2.12-2.22 (m, 2H), 1.78-1.83 (m,2H), 1.53-1.66 (m, 4H), 1.36 (d, J = 6.88 Hz, 6H). MS (ESI) m/z: 571.3(M + H)⁺ 33

¹H NMR (500 MHz, CD₃OD) δ 7.62 (d, J = 8.80 Hz, 2H), 7.58 (d, J = 8.53Hz, 1H), 7.34 (t, J = 7.70 Hz, 1H), 7.06 (t, J = 7.98 Hz, 1H), 7.03 (d,J = 8.25 Hz, 1H), 6.97 (d, J = 9.08 Hz, 2H), 4.91 (sept, J = 6.60 Hz,1H), 4.19 (d, J = 17.61 Hz, 1H), 3.99 (t, J = 6.33 Hz, 2H), 3.88 (d, J =17.61 Hz, 1H), 2.11-2.21 (m, 2H), 1.76- 1.82 (m, 2H), 1.52-1.64 (m, 4H),1.43 (d, J = 6.60 Hz, 6H). MS (ESI) m/z: 622.4 (M + H)⁺. 34

¹H NMR (500 MHz, CD₃OD) δ 7.59 (d, J = 8.80 Hz, 2H), 7.43 (d, J = 8.25Hz, 1H), 7.40 (s, 1H), 7.14 (t, J = 7.43 Hz, 1H), 6.95 (d, J = 9.08 Hz,2H), 6.94 (t, J = 6.33 Hz, 1H), 6.89 (d, J = 7.98 Hz, 1H), 4.70 (sept, J= 6.88 Hz, 1H), 3.98 (t, J = 6.33 Hz, 2H), 3.89 (d, J = 17.33 Hz, 1H),3.84 (d, J = 17.06 Hz, 1H), 2.11-2.21 (m, 2H), 1.76-1.82 (m, 2H),1.52-1.65 (m, 4H), 1.45 (d, J = 6.60 Hz, 6H). MS (ESI) m/z: 621.3 (M +H)⁺. 35

¹H NMR (500 MHz, DMSO-d₆) δ 9.35 (br. s., 1H), 7.52 (d, J = 8.5 Hz, 2H),7.02 (d, J = 6.6 Hz, 2H), 7.00 (s, 1H), 4.22 (d, J = 17.1 Hz, 1H), 4.05(t, J = 6.1 Hz, 2H), 3.48 (d, J = 17.1 Hz, 1H), 2.84 (s, 6H), 2.44-2.33(m, 2H), 1.98-1.88 (m, 2H). MS (ESI) m/z: 562.2 (M + H)⁺. 36

¹H NMR (500 MHz, DMSO-d₆) δ 9.68 (s, 1H), 8.34 (s, 1H), 7.63 (d, J = 8.5Hz, 2H), 7.50 (d, J = 8.0 Hz, 1H), 7.02 (d, J = 8.8 Hz, 2H), 6.91 (d, J= 7.4 Hz, 1H), 4.06 (t, J = 6.1 Hz, 2H), 3.95-3.84 (m, 1H), 3.69 (d, J =17.9 Hz, 1H), 2.45-2.34 (m, 2H), 2.26 (s, 3H), 1.99-1.86 (m, 2H). MS(ESI) m/z: 527.2 (M + H)⁺. 37

¹H NMR (500 MHz, DMSO-d₆) δ 9.58 (br. s., 1H), 8.35 (s, 1H), 7.62 (d, J= 8.5 Hz, 2H), 7.44 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 8.5 Hz, 2H), 6.81(d, J = 8.0 Hz, 1H), 4.06 (t, J = 6.1 Hz, 2H), 3.94- 3.83 (m, 1H), 3.65(d, J = 18.2 Hz, 1H), 2.46-2.33 (m, 2H), 2.25 (s, 3H), 2.01-1.84 (m,2H). MS (ESI) m/z: 527.2 (M + H)⁺. 38

¹H NMR (500 MHz, CDCl₃) δ 8.63 (d, J = 0.8 Hz, 2H), 7.55 (d, J = 8.8 Hz,2H), 6.98-6.88 (m, 2H), 6.72 (s, 1H), 4.10 (d, J = 19.0 Hz, 1H), 4.02(t, J = 6.1 Hz, 2H), 3.77 (d, J = 18.7 Hz, 1H), 2.39 (s, 3H), 2.36-2.23(m, 2H), 2.10-2.02 (m, 2H). MS (ESI) m/z: 528.1 (M + H)⁺. 39

¹H NMR (500 MHz, DMSO-d₆) δ 9.52 (s, 1H), 7.72 (d, J = 2.1 Hz, 1H), 7.57(t, J = 9.2 Hz, 1H), 6.97-6.87 (m, 2H), 5.44 (s, 1H), 4.50-4.40 (m, 1H),4.30 (d, J = 17.4 Hz, 1H), 4.10 (t, J = 6.1 Hz, 2H), 3.57 (d, J = 17.7Hz, 1H), 2.49-2.35 (m, 2H), 2.01-1.87 (m, 2H), 1.31 (t, J = 6.9 Hz, 6H).MS (ESI) m/z: 562.2 (M + H)⁺. 40

¹H NMR (500 MHz, DMSO-d₆) δ 9.54 (br. s., 1H), 7.96 (s, 1H), 7.74 (br.s., 1H), 7.57 (t, J = 9.0 Hz, 1H), 6.99-6.87 (m, 2H), 5.46 (br. s., 1H),4.78 (quin, J = 8.2 Hz, 1H), 4.30 (d, J = 17.4 Hz, 1H), 4.09 (t, J = 5.5Hz, 2H), 3.58 (d, J = 17.4 Hz, 1H), 2.48-2.36 (m, 2H), 2.35-2.22 (m,4H), 2.01- 1.88 (m, 2H), 1.81-1.68 (m, 2H). MS (ESI) m/z: 574.2 (M +H)⁺. 41

¹H NMR (500 MHz, DMSO-d₆) δ 9.33 (br. s., 1H), 7.64 (s, 1H), 7.54 (t, J= 9.2 Hz, 1H), 6.93- 6.86 (m, 2H), 5.13 (br. s., 1H), 4.25 (d, J = 17.4Hz, 1H), 4.08 (t, J = 5.8 Hz, 2H), 3.76-3.68 (m, 1H), 3.49 (d, J = 17.7Hz, 1H), 2.47-2.31 (m, 2H), 1.99-1.86 (m, 2H), 0.98-0.85 (m, 4H). MS(ESI) m/z: 560.3 (M + H)⁺. 42

¹H NMR (500 MHz, DMSO-d₆) δ 9.52 (s, 1H), 7.70 (d, J = 2.5 Hz, 1H), 7.58(t, J = 8.7 Hz, 1H), 7.21-7.09 (m, 2H), 5.21 (d, J = 1.9 Hz, 1H), 4.31(d, J = 17.6 Hz, 1H), 4.01-3.83 (m, 2H), 3.62 (d, J = 17.6 Hz, 1H), 2.64(t, J = 7.7 Hz, 2H), 2.36-2.18 (m, 2H), 1.72- 1.61 (m, 2H), 1.57-1.41(m, 2H), 1.20-1.06 (m, 1H), 0.53- 0.44 (m, 2H), 0.37-0.28 (m, 2H). MS(ESI) m/z: 572.4 (M + H)⁺. 43

¹H NMR (500 MHz, DMSO-d₆) δ 9.45 (s, 1H), 7.60 (s, 1H), 7.49 (t, J = 9.2Hz, 1H), 6.85 (d, J = 11.6 Hz, 2H), 5.17 (br. s., 1H), 4.22 (d, J = 17.4Hz, 2H), 4.06-3.98 (m, 4H), 3.51 (d, J = 17.7 Hz, 1H), 2.40-2.25 (m,2H), 1.93-1.80 (m, 2H), 1.22 (t, J = 7.2 Hz, 3H). MS (ESI) m/z: 548.1(M + H)⁺. 44

¹H NMR (500 MHz, DMSO-d₆) δ 7.62 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 3.4Hz, 1H), 6.99 (d, J = 8.8 Hz, 2H), 6.74 (d, J = 3.7 Hz, 1H), 4.02 (t, J= 6.1 Hz, 2H), 3.94- 3.79 (m, 1H), 3.62-3.46 (m, 1H), 2.40-2.24 (m, 2H),2.02-1.91 (m, 1H), 1.83-1.77 (m, 2H), 1.66- 1.57 (m, 2H), 0.98-0.88 (m,2H), 0.59-0.44 (m, 2H). MS (ESI) m/z: 572.1 (M + H)⁺. 45

¹H NMR (500 MHz, DMSO-d₆) δ 9.44 (br. s., 1H), 7.48 (d, J = 8.2 Hz, 2H),7.05 (s, 1H), 6.97 (d, J = 8.2 Hz, 2H), 4.21 (d, J = 17.1 Hz, 1H), 3.98(t, J = 6.0 Hz, 2H), 3.51 (d, J = 17.1 Hz, 1H), 2.84 (s, 6H), 2.32-2.14(m, 2H), 1.84-1.69 (m, 2H), 1.67-1.53 (m, 2H). MS (ESI) m/z: 576.1 (M +H)⁺. 46

¹H NMR (500 MHz, DMSO-d₆) δ 9.58 (br. s., 1H), 7.76 (br. s., 1H), 7.63(br. t, J = 7.3 Hz, 1H), 7.27- 7.18 (m, 2H), 5.50 (br. s, 1H), 4.56-4.43(m, 1H), 4.35 (d, J = 17.7 Hz, 1H), 3.67 (d, J = 17.7 Hz, 1H), 2.71 (t,J = 6.6 Hz, 2H), 2.41-2.24 (m, 2H), 1.78-1.67 (m, 2H), 1.62-1.49 (m,2H), 1.41- 1.31 (m, 6H). MS (ESI) m/z: 560.6 (M + H)⁺. 47

¹H NMR (500 MHz, DMSO-d₆) δ 9.57 (br. s., 1H), 7.74 (br. s., 1H), 7.58(t, J = 8.4 Hz, 1H), 7.22- 7.12 (m, 2H), 5.41 (br. s., 1H), 4.83-4.73(m, 1H), 4.30 (d, J = 17.8 Hz, 1H), 3.61 (d, J = 17.5 Hz, 1H), 2.64 (t,J = 7.6 Hz, 2H), 2.35-2.19 (m, 6H), 1.78-1.71 (m, 2H), 1.70-1.61 (m,2H), 1.55-1.45 (m, 2H). MS (ESI) m/z: 572.6 (M + H)⁺. 48

¹H NMR (500 MHz, DMSO-d₆) δ 9.11 (br. s., 1H), 7.95 (s, 1H), 7.58 (t, J= 8.2 Hz, 1H), 7.20- 7.11 (m, 2H), 7.07 (br. s., 1H), 6.74 (br. s., 1H),4.87 (br. s., 1H), 4.25-4.14 (m, 1H), 3.97 (d, J = 17.2 Hz, 1H), 3.44(d, J = 17.2 Hz, 1H), 2.64 (t, J = 7.6 Hz, 2H), 2.35-2.18 (m, 2H),1.72-1.61 (m, 2H), 1.55-1.44 (m, 2H), 1.28 (d, J = 6.1 Hz, 6H). MS (ESI)m/z: 559.6 (M + H)⁺. 49

¹H NMR (500 MHz, DMSO-d₆) δ 9.57 (br. s., 1H), 7.95 (s, 1H), 7.68 (s,1H), 7.57 (t, J = 5.7 Hz, 1H), 7.23-7.08 (m, 2H), 5.24 (s, 1H), 4.29 (d,J = 17.5 Hz, 1H), 4.16-4.01 (m, 2H), 3.62 (d, J = 17.2 Hz, 1H),2.69-2.57 (m, 2H), 2.35-2.18 (m, 2H), 1.73-1.59 (m, 2H), 1.58-1.42 (m,2H), 1.35-1.20 (m, 3H). MS (ESI) m/z: 546.6 (M + H)⁺. 50

¹H NMR (500 MHz, DMSO-d₆) δ 9.55 (s, 1H), 7.64 (s, 1H), 7.56 (t, J = 8.4Hz, 1H), 7.20-7.08 (m, 2H), 5.24 (s, 1H), 4.31 (d, J = 17.4 Hz, 1H),3.88 (d, J = 7.0 Hz, 2H), 3.60 (d, J = 17.7 Hz, 1H), 2.64 (t, J = 7.5Hz, 2H), 2.34-2.18 (m, 2H), 2.05-1.90 (m, 1H), 1.71-1.60 (m, 2H), 1.55-1.44 (m, 2H), 0.78 (d, J = 6.4 Hz, 6H). MS (ESI) m/z: 574.5 (M + H)⁺. 51

¹H NMR (500 MHz, DMSO-d₆) δ 9.43 (s, 1H), 7.58 (d, J = 1.8 Hz, 1H), 7.51(t, J = 9.3 Hz, 1H), 6.90-6.81 (m, 2H), 5.15 (s, 1H), 4.28 (d, J = 17.1Hz, 1H), 4.04 (t, J = 6.0 Hz, 2H), 3.84 (d, J = 6.7 Hz, 2H), 3.50 (d, J= 17.4 Hz, 1H), 2.41-2.33 (m, 2H), 2.00-1.94 (m, 1H), 1.94-1.85 (m, 2H),0.75 (d, J = 6.4 Hz, 6H). MS (ESI) m/z: 576.5 (M + H)⁺. 52

¹H NMR (500 MHz, DMSO-d₆) δ 9.51 (s, 1H), 7.68 (d, J = 2.4 Hz, 1H), 7.53(t, J = 9.2 Hz, 1H), 6.94-6.80 (m, 2H), 5.24 (d, J = 2.4 Hz, 1H), 4.30(d, J = 17.7 Hz, 1H), 4.06 (t, J = 6.0 Hz, 2H), 3.97-3.83 (m, 2H), 3.57(d, J = 17.1 Hz, 1H), 2.45-2.32 (m, 2H), 1.97-1.86 (m, 2H), 1.16-1.06(m, 1H), 0.47 (d, J = 7.9 Hz, 2H), 0.33-0.23 (m, 2H). MS (ESI) m/z:574.5 (M + H)⁺. 53

¹H NMR (500 MHz, DMSO-d₆) δ 9.45 (s, 1H), 7.56 (d, J = 2.1 Hz, 1H), 7.47(t, J = 9.2 Hz, 1H), 6.88-6.78 (m, 2H), 5.14 (d, J = 1.5 Hz, 1H), 4.24(d, J = 17.7 Hz, 1H), 4.05-3.98 (m, 4H), 3.50 (d, J = 17.7 Hz, 1H),2.60-2.51 (m, 1H), 2.40-2.27 (m, 2H), 1.91- 1.81 (m, 4H), 1.80-1.69 (m,2H), 1.67-1.56 (m, 2H). MS (ESI) m/z: 588.6 (M + H)⁺. 54

¹H NMR (500 MHz, CDCl₃) δ 7.32-7.22 (m, 2H), 6.92 (br. s., 1H),6.74-6.63 (m, 3H), 4.09 (d, J = 17.9 Hz, 1H), 4.00 (t, J = 5.9 Hz, 2H),3.54 (d, J = 18.2 Hz, 1H), 2.36-2.23 (m, 2H), 2.10- 1.97 (m, 3H),1.12-1.04 (m, 2H), 0.80-0.73 (m, 2H). MS (ESI) m/z: 576.2 (M + H)⁺. 55

¹H NMR (500 MHz, DMSO-d₆) δ 8.01 (s, 1H), 7.74 (s, 1H), 7.36 (d, J = 3.1Hz, 1H), 6.73 (d, J = 3.7 Hz, 1H), 4.10 (t, J = 6.9 Hz, 2H), 3.62 (d, J= 17.7 Hz, 1H), 3.53 (d, J = 17.7 Hz, 1H), 2.27-2.11 (m, 2H), 2.01-1.93(m, 1H), 1.83- 1.73 (m, 2H), 1.52-1.39 (m, 2H), 1.34-1.20 (m, 2H), 0.95(d, J = 6.1 Hz, 2H), 0.56 (d, J = 4.6 Hz, 2H). MS (ESI) m/z: 560.4 (M +H)⁺. 56

¹H NMR (500 MHz, CDCl₃) δ 7.47 (d, J = 8.8 Hz, 1H), 7.25 (d, J = 3.9 Hz,1H), 7.07-7.02 (m, 1H), 7.00 (d, J = 2.8 Hz, 1H), 6.88-6.81 (m, 1H),6.74-6.68 (m, 1H), 4.27-4.15 (m, 1H), 4.03 (s, 2H), 3.57 (d, J = 18.4Hz, 1H), 2.39-2.26 (m, 2H), 2.15-2.02 (m, 3H), 1.13-1.05 (m, 2H),0.81-0.73 (m, 2H). MS (ESI) m/z 592.0 (M + H)⁺. 57

¹H NMR (500 MHz, CDCl₃) δ 8.00-7.95 (m, 1H), 7.27 (d, J = 8.8 Hz, 1H),7.21 (d, J = 3.9 Hz, 1H), 6.72 (d, J = 3.9 Hz, 1H), 6.56 (d, J = 2.5 Hz,1H), 6.53- 6.48 (m, 1H), 4.09-3.96 (m, 3H), 3.92 (s, 3H), 3.67 (s, 1H),2.41- 2.25 (m, 2H), 2.13-2.02 (m, 3H), 1.09 (dd, J = 8.3, 1.9 Hz, 2H),0.83-0.75 (m, 2H). MS (ESI) m/z: 588.0 (M + H)⁺. 58

¹H NMR (500 MHz, DMSO-d₆) δ 9.44 (br. s., 1H), 7.56 (br. s., 3H), 6.96(br. s., 2H), 6.82 (br. s., 1H), 3.95 (br. s., 2H), 2.97 (br. s., 1H),2.60 (br. s., 2H), 2.19 (d, J = 10.1 Hz, 2H), 1.70 (br. s., 2H), 1.63(br. s., 1H), 1.40-1.56 (m, 4H), 1.05 (br. s., 3H). MS (ESI) m/z: 574.2(M + H)⁺. 59

¹H NMR (500 MHz, CDCl₃) δ 7.66 (s, 1H), 7.43 (t, J = 9.1 Hz, 1H),6.73-6.56 (m, 2H), 4.58 (d, J = 18.2 Hz, 1H), 3.98 (t, J = 5.6 Hz, 2H),3.68 (d, J = 18.2 Hz, 1H), 2.38-2.20 (m, 2H), 2.12- 1.93 (m, 3H),1.18-1.07 (m, 2H), 0.78 (br. s., 2H). MS (ESI) m/z: 577.1 (M + H)⁺. 60

¹H NMR (500 MHz, DMSO-d₆) δ 9.95 (s, 1H), 8.14 (d, J = 8.2 Hz, 1H), 8.05(d, J = 7.9 Hz, 1H), 7.59 (d, J = 8.5 Hz, 3H), 7.46- 7.54 (m, 1H), 7.02(d, J = 8.5 Hz, 2H), 4.28 (d, J = 17.7 Hz, 1H), 3.86-4.08 (m, 3H),2.17-2.32 (m, 2H), 1.66-1.81 (m, 2H), 1.40-1.62 (m, 4H). MS (ESI) m/z:597.1 (M + H)⁺. 61

¹H NMR (500 MHz, CDCl₃) δ 7.66 (d, J = 9.1 Hz, 1H), 7.43 (d, J = 2.5 Hz,1H), 6.98-6.92 (m, 2H), 6.79 (dd, J = 9.1, 2.8 Hz, 1H), 6.42 (d, J = 2.5Hz, 1H), 4.56 (d, J = 19.0 Hz, 1H), 4.00 (t, J = 5.9 Hz, 2H), 3.66 (dt,J = 7.4, 3.6 Hz, 1H), 3.55 (d, J = 18.7 Hz, 1H), 2.36-2.21 (m, 2H),2.10- 2.02 (m, 2H), 1.23-1.16 (m, 2H), 1.13-1.06 (m, 2H). MS (ESI) m/z:576.0 (M + H)⁺. 62

¹H NMR (400 MHz, CD₃OD) δ 7.73-7.67 (m, 1H), 7.55 (t, J = 9.2 Hz, 1H),6.90-6.80 (m, 2H), 4.60 (dd, J = 17.6, 1.3 Hz, 1H), 4.10 (t, J = 6.1 Hz,2H), 3.75 (d, J = 17.7 Hz, 1H), 2.85 (q, J = 7.5, 1.0 Hz, 2H), 2.45-2.30(m, 2H), 2.10-2.01 (m, 2H), 1.25 (t, J = 7.5 Hz, 3H). MS (ESI) m/z:565.3 (M + H)⁺. 63

¹H NMR (500 MHz, DMSO-d₆) δ 9.36 (br. s., 1H), 7.67 (s, 1H), 7.53 (d, J= 8.5 Hz, 1H), 7.14 (br. s., 1H), 7.01 (d, J = 9.2 Hz, 1H), 4.27 (d, J =18.6 Hz, 1H), 4.03 (br. s., 2H), 3.72 (d, J = 19.2 Hz, 1H), 2.25 (br.s., 2H), 2.07 (br. s., 1H), 1.74 (br. s., 2H), 1.60-1.39 (m, 4H), 1.00(d, J = 7.3 Hz, 2H), 0.61 (br. s., 2H). MS (ESI) m/z: 621.1 (M + H)⁺. 64

¹H NMR (500 MHz, DMSO-d₆) δ 9.54 (s, 1H), 7.72 (s, 1H), 7.54 (d, J = 8.5Hz, 1H), 7.25-7.13 (m, 1H), 7.10-6.96 (m, 1H), 4.24 (d, J = 18.9 Hz,1H), 4.10 (t, J = 6.1 Hz, 2H), 3.78 (d, J = 19.2 Hz, 1H), 2.42 (dd, J =16.3, 11.4 Hz, 2H), 2.17-2.05 (m, 1H), 1.98- 1.82 (m, 2H), 1.13-0.89 (m,2H), 0.69-0.55 (m, 2H). MS (ESI) m/z: 593.0 (M + H)⁺. 65

¹H NMR (500 MHz, DMSO-d₆) δ 9.64 (s, 2H), 6.89 (d, J = 4.1 Hz, 2H), 3.98(d, J = 17.2 Hz, 1H), 3.68 (d, J = 17.5 Hz, 1H), 2.66 (q, J = 7.5 Hz,2H), 1.08 (t, J = 7.5 Hz, 3H). MS (ESI) m/z: 500.2 (M + H)⁺. 66

¹H NMR (500 MHz, DMSO-d₆) δ 9.81 (s, 1H), 7.77 (s, 1H), 7.50 (t, J = 9.2Hz, 1H), 6.99-6.79 (m, 2H), 4.45 (d, J = 17.6 Hz, 1H), 3.99 (t, J = 6.4Hz, 2H), 3.72 (d, J = 17.9 Hz, 1H), 2.76 (q, J = 7.4 Hz, 2H), 2.32-2.15(m, 2H), 1.79- 1.65 (m, 2H), 1.57-1.37 (m, 4H), 1.11 (t, J = 7.4 Hz,3H). MS (ESI) m/z: 593.3 (M + H)⁺.

Example 67(S)-4-(5-Methylthiophen-2-yl)-2-oxo-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-1,2,5,6-tetrahydropyridine-3-carbonitrile

67A. (R)-Methyl3-((S)-1,1-dimethylethylsulfinamido)-4,4,4-trifluoro-3-(4-(4,4,4-trifluorobutoxy)phenyl)butanoate:To a solution of methyl acetate (3.54 g, 47.8 mmol) in ether (335 mL)was added KHMDS in THF (35.8 mL, 35.8 mmol) dropwise over 10 min at −78°C. The reaction mixture was stirred at −78° C. for 30 min. At −78° C., asolution of Intermediate 1 (9.64 g, 23.90 mmol) in ether (335 mL) wasadded dropwise over 20 min. and the reaction mixture was stirred at −78°C. for 1 h. The reaction mixture was quenched with sat. aq. NaCl (400mL). The reaction mixture was diluted with ether (400 mL) and sat. aq.NaCl (400 mL). The organic phase was dried over MgSO₄ and concentratedto a yellow oil that was purified by chromatography to give the desiredproduct as a clear oil (9.8873 g, 87% yield). LCMS Anal. Calc'd forC₁₉H₂₅F₆NO₄S, 477.14. found [M+H] 478.2.

67B. (5)-Methyl3-amino-4,4,4-trifluoro-3-(4-(4,4,4-trifluorobutoxy)phenyl) butanoate:To a solution of 67A (9.3151 g, 19.51 mmol) in MeOH (230 mL) was addedHCl in dioxane (24.39 mL, 98 mmol) and the reaction mixture was stirredat rt for 1 h. The reaction solvent was removed under vacuum, theresidue was dissolved in EtOAc (30 mL) and the solution was washed withsat. aq. NaHCO₃ (20 mL). The organic phase was dried over MgSO₄ andconcentrated in vacuo to give the desired product as pale yellow oil(7.7 g, 105% yield). LCMS Anal. Calc'd for C₁₅H₁₇F₆NO₃, 373.11. found[M+H] 374.0.

67C. (S)-Methyl3-(2-cyanoacetamido)-4,4,4-trifluoro-3-(4-(4,4,4-trifluorobutoxy)phenyl)butanoate:To a solution of 2-cyanoacetyl chloride (7.25 g, 19.42 mmol) in DCM (400mL) was added pyridine (9.42 mL, 117 mmol) followed by a solution of 67B(8.04 g, 78 mmol) in DCM (100 mL). The reaction mixture was stirred atrt for 1 h. The reaction solvent was removed under vacuum, the residuewas dissolved in EtOAc (2×60 mL) and the solution was washed with sat.aq. NH₄Cl (50 mL). The organic phase was dried over MgSO₄ andconcentrated. The residue was purified by chromatography to give thedesired product as a pale yellow oil (7.03 g, 82% yield). LCMS Anal.Calc'd for C₁₈H₁₈F₆N₂O₄, 440.12. found [M+H] 441.0.

67D.(S)-4-Hydroxy-2-oxo-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-1,2,5,6-tetrahydropyridine-3-carbonitrile:To a solution of 67C (7.0257 g, 15.96 mmol) in MeOH (200 mL) was addedsodium methoxide (18.26 mL, 80 mmol) and the reaction mixture wasstirred at 55° C. for 2 h. The reaction solvent was removed undervacuum, the residue was dissolved in EtOAc (100 mL) and the solution waswashed with 1N HCl (100 mL). The organic phase was dried over MgSO₄ andconcentrated in vacuo to give the desired product as a yellow solid(6.966, 107% yield). LCMS Anal. Calc'd for C₁₇H₁₄F₆N₂O₃, 408.09. found[M+H] 409.0.

67E.(S)-4-Chloro-2-oxo-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-1,2,5,6-tetrahydropyridine-3-carbonitrile:To a solution of 67D (5.47 g, 13.40 mmol) in DCE (550 mL) was addedPOCl₃ (1.499 mL, 16.08 mmol) and DIEA (3.28 mL, 18.76 mmol) and thereaction mixture was stirred at rt for 30 min. and heated to 85° C. for3 h. The reaction mixture was concentrated in vacuo to a yellow oil thatwas dissolved in EtOAc (100 mL), washed with sat. aq. NH₄Cl (50 mL),dried over MgSO₄ and concentrated. The residue was purified bychromatography to give the desired product as a yellow solid (3.7334 g,65.3% yield). LCMS Anal. Calc'd for C₁₇H₁₃F₆ClN₂O₂ 426.06. found [M+H]427.0.

Example 67

To a vial was added 1,1′-bis(di-tert-butylphosphino)ferrocene palladiumdichloride (4.58 mg, 7.03 μmol), CsF (21.36 mg, 0.141 mmol), dioxane(0.499 mL), (5-methylthiophen-2-yl)boronic acid (10 mg, 0.0709 mmol) and67E (20 mg, 0.0937 mmol). The reaction mixture stirred at 80° C. in asealed vial for 1.5 h. The solvent was removed in vacuo. The residue waspurified by prep HPLC to yield Example 28 (1.1 mg, 0.002 mmol, 3.2%yield). LCMS Anal. Calc'd for C₂₂H₁₈F₆N₂O₂S, 488.10. found [M+H] 488.8.¹H NMR (500 MHz, 1:1 CDCl₃:MeOD) δ 7.94 (d, J=4.0 Hz, 1H), 7.45 (d,J=8.9 Hz, 2H), 7.03-6.96 (m, 1H), 6.94 (d, J=8.9 Hz, 2H), 4.03 (t, J=5.9Hz, 2H), 3.79 (d, J=16.8 Hz, 1H), 3.56 (d, J=17.3 Hz, 1H), 2.62-2.58 (m,3H), 2.40-2.23 (m, 2H), 2.08-1.98 (m, 2H).

The following Examples in Table 3 were prepared in a similar manner asExample 67 utilizing Intermediate 1, 2, 4 and different commerciallyavailable heterocyclic boronic acids.

TABLE 3 Example No. Structure and Name Analytical Data 68

¹H NMR (500 MHz, 1:1 CDCl₃: MeOD) δ 7.95-7.87 (m, 1H), 7.48- 7.42 (m,2H), 7.18-7.12 (m, 1H), 6.96-6.88 (m, 2H), 4.11-3.98 (m, 2H), 3.81-3.70(m, 1H), 3.56 (d, J = 17.3 Hz, 1H), 2.42-2.21 (m, 2H), 2.12-1.96 (m,2H). MS(ESI) m/z: 509.4 (M + H)⁺. (S)-4-(5-Chlorothiophen-2-yl)-2-oxo-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6- (trifluoromethyl)-1,2,5,6-tetrahydropyridine-3-carbonitrile 69

¹H NMR (500 MHz, 1:1 CDCl₃: MeOD) δ 7.95-7.88 (m, 1H), 7.52- 7.38 (m,3H) 6.98-6.88 (m 2H) 4.09-3.98 (m, 2H), 3.81-3.71 (m, 1H), 3.58 (d, J =17.3 Hz, 1H), 2.42- 2.24 (m, 5H), 2.09-1.97 (m, 2H). MS(ESI) m/z: 489.11(M + H)⁺. (S)-4-(4-Methylthiophen-2-yl)-2-oxo-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6- (trifluoromethyl)-1,2,5,6-tetrahydropyridine-3-carbonitrile 70

¹H NMR (500 MHz, DMSO-d₆) δ 9.82 (s, 1H), 8.65-8.44 (m, 1H), 8.03 (dd, J= 8.9, 2.7 Hz, 1H), 7.61 (d, J = 8.5 Hz, 2H), 7.01 (d, J = 8.5 Hz, 3H),4.02 (t, J = 6.4 Hz, 2H), 3.94 (s, 3H), 3.88 (s, 1H), 3.73 (d, J = 18.3Hz, 1H), 2.40-2.26 (m, 2H), 1.84-1.72 (m, 2H), 1.64 (d, J = 7.3 Hz, 2H).MS(ESI) m/z: 514.2 (M + H)⁺. (S)-6-Methoxy-2′-oxo-6′-(trifluoromethyl)-6′-(4-((5,5,5-trifluoropentyl)oxy)phenyl)-1′,2′,5′,6′-tetrahydro-[3,4′-bipyridine]-3′- carbonitrile 71

¹H NMR (500 MHz, DMSO-d₆) δ 9.73 (s, 1H), 8.16 (d, J = 3.7 Hz, 1H), 7.54(d, J = 8.8 Hz, 2H), 7.16- 7.04 (m, 1H), 6.97 (d, J = 9.1 Hz, 2H), 3.97(s, 2H), 3.68-3.62 (m, 1H), 3.48-3.35 (m, 1H), 2.56 (s, 3H), 2.32-2.14(m, 2H), 1.79-1.63 (m, 2H), 1.58-1.36 (m, 4H). MS(ESI) m/z: 517.1 (M +H)⁺. (S)-4-(5-Methylthiophen-2-yl)-2-oxo-6-(4-((6,6,6-trifluorohexyl)oxy)phenyl)-6- (trifluoromethyl)-1,2,5,6-tetrahydropyridine-3-carbonitrile 72

¹H NMR (400 MHz, DMSO-d₆) δ 9.78 (s, 1H), 8.53 (d, J = 2.2 Hz, 1H), 8.04(dd, J = 8.8, 2.6 Hz, 1H), 7.61 (d, J = 8.8 Hz, 2H), 7.00 (dd, J = 8.9,2.8 Hz, 3H), 4.00 (t, J = 6.4 Hz, 2H), 3.94 (s, 3H), 3.87-3.84 (m, 1H),3.73 (d, J = 18.3 Hz, 1H), 2.35-2.17 (m, 2H), 1.74 (quin, J = 6.7 Hz,2H), 1.62-1.41 (m, 4H). (S)-6-Methoxy-2′-oxo-6′-(4-((6,6,6-trifluorohexyl)oxy)phenyl)-6′- (trifluoromethyl)-1′,2′,5′,6′-tetrahydro-[3,4′-bipyridine]-3′-carbonitrile 73

¹H NMR (500 MHz, 1:1 CDCl₃: MeOD) δ 8.44 (d, J = 2.5 Hz, 1H), 7.90 (dd,J = 8.7, 2.7 Hz, 1H), 7.48 (d, J = 8.9 Hz, 2H), 6.97 (d, J = 8.9 Hz,2H), 6.90 (d, J = 8.9 Hz, 1H), 4.06 (t, J = 5.9 Hz, 2H), 3.99 (s, 3H),3.97-3.88 (m, 1H), 3.63 (d, J = 8.4 Hz, 1H), 2.33 (d, J = 5.0 Hz, 2H),2.11-1.99 (m, 2H). (S)-6-Methoxy-2′-oxo-6′-(4-(4,4,4-trifluorobutoxy)phenyl)-6′- (trifluoromethyl)-1′,2′,5′,6′-tetrahydro-[3,4′-bipyridine]-3′-carbonitrile

Example 74(S)-4-(5-Cyclopropylthiophen-2-yl)-2-oxo-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-1,2,5,6-tetrahydropyridine-3-carbonitrile

To a solution of Example 2B (30.0 mg, 0.064 mmol) andN,N′-methanediylidenedicyclohexanamine (39.9 mg, 0.193 mmol) in THF(0.555 mL) was added a solution of 2-cyanoacetic acid (16.45 mg, 0.193mmol) in THF (0.555 mL) and the reaction mixture stirred at rt underargon for 2 h. The solvent was removed in vacuo and the residue wastaken up in EtOAc (10 mL). The solution was washed with water (1×10 mL)followed by sat. Na₂CO₃ (2×10 mL). The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated. Purification by Prep HPLCafforded Example 35 (9.9 mg, 28%). LCMS Anal. Calc'd for C₂₄H₂₀F₆N₂O₂S,514.11. found [M+H] 515.1. ¹H NMR (500 MHz, DMSO-d₆) δ 9.67 (s, 1H),8.15 (d, J=4.1 Hz, 1H), 7.55 (d, J=8.8 Hz, 2H), 7.05 (d, J=4.1 Hz, 1H),6.98 (d, J=8.8 Hz, 2H), 4.03 (t, J=6.2 Hz, 2H), 3.98 (d, J=17.6 Hz, 1H),3.62 (d, J=17.3 Hz, 1H), 2.45-2.33 (m, 2H), 2.31-2.23 (m, 1H), 1.94-1.79(m, 2H), 1.23-1.11 (m, 2H), 0.87-0.77 (m, 2H).

Example 75(S)—N-(4-(5-Ethylthiophen-2-yl)-2-oxo-6-(4-((6,6,6-trifluorohexyl)oxy)phenyl)-6-(trifluoromethyl)-1,2,5,6-tetrahydropyridin-3-yl)-2-(methylsulfonyl)acetamide

75A.(S)-3-Amino-1-(5-ethylthiophen-2-yl)-4,4,4-trifluoro-3-(4-((6,6,6-trifluorohexyl)oxy)phenyl)butan-1-one:75A was prepared in a similar manner as Example 1A and 1B. ¹H NMR (400MHz, CDCl₃) δ 7.58 (d, J=4.0 Hz, 1H), 7.50 (d, J=8.8 Hz, 2H), 6.86 (d,J=8.8 Hz, 3H), 3.95 (t, J=6.3 Hz, 2H), 3.87 (d, J=16.5 Hz, 1H), 3.42 (d,J=16.5 Hz, 1H), 2.88 (q, J=7.6 Hz, 2H), 2.19-2.04 (m, 2H), 1.84-1.75 (m,2H), 1.69-1.50 (m, 4H), 1.33 (t, J=7.6 Hz, 3H).

75B.(S)-2-(1,3-Dioxoisoindolin-2-yl)-N-(4-(5-ethylthiophen-2-yl)-1,1,1-trifluoro-4-oxo-2-(4-((6,6,6-trifluorohexyl)oxy)phenyl)butan-2-yl)acetamide:Chloroacetonitrile (0.044 mL, 0.436 mmol) was added dropwise to asolution of 2-(1,3-dioxoisoindolin-2-yl)acetic acid (59.7 mg, 0.291mmol) and triphenylphosphine (153 mg, 0.582 mmol) in DCM (2 mL) andstirred at rt for 1 h. Then, a solution of 75A (70 mg, 0.145 mmol) inDCM (1 mL) followed by pyridine (0.035 mL, 0.436 mmol) were added andstirred at rt for 1 h. Concentrated and the crude was purified usingISCO flash chromatography to give 75B (86 mg, 0.129 mmol, 88% yield) asa white foam. ¹H NMR (400 MHz, CDCl₃) δ 7.89 (dd, J=5.5, 3.1 Hz, 2H),7.77 (s, 1H), 7.73 (dd, J=5.5, 3.1 Hz, 2H), 7.45 (d, J=3.7 Hz, 1H), 7.39(d, J=8.6 Hz, 2H), 6.87 (d, J=9.0 Hz, 2H), 6.81 (d, J=4.0 Hz, 1H), 4.49,4.46 (ABq, J=16.1 Hz, 2H), 3.94 (t, J=6.3 Hz, 2H), 3.82 (d, J=15.4 Hz,1H), 3.40 (d, J=15.4 Hz, 1H), 2.87 (q, J=7.8 Hz, 2H), 2.18-2.04 (m, 2H),1.84-1.75 (m, 2H), 1.69-1.51 (m, 4H), 1.33 (t, J=7.5 Hz, 3H).

75C.(S)-3-Amino-4-(5-ethylthiophen-2-yl)-6-(4-((6,6,6-trifluorohexyl)oxy)phenyl)-6-(trifluoromethyl)-5,6-dihydropyridin-2(1H)-one: A mixture of75B (86 mg, 0.129 mmol) and 1N NaOH (0.270 mL, 0.270 mmol) in MeOH (1mL) was stirred under microwave at 130° C. for 15 min. Acidified with 1NHCl, diluted with DCM, washed with water, dried (MgSO₄), andconcentrated. The crude mixture was dissolved in EtOH (1 mL) and 33%methylamine in ethanol (0.3 mL, 2.58 mmol) was added and stirred at 80°C. for 3 h and stirred at 60° C. overnight. 0.3 mL of methylamine wasadded and stirred at 80° C. for 5 h. The mixture was concentrated,diluted with DCM, washed with 1N NaOH, dried (MgSO₄), and concentratedto give 75C (53 mg, 0.102 mmol, 79% yield) as a yellow-brown gum. LCMSAnal. Calc'd for C₂₄H₂₆F₆N₂O₂S, 520.16. found [M+H] 521.3.

Example 75

Trichloroacetonitrile (0.029 mL, 0.288 mmol) was added dropwise to asolution of 2-(methylsulfonyl)acetic acid (26.5 mg, 0.192 mmol) andtriphenylphosphine (101 mg, 0.384 mmol) in DCM (1 mL) and stirred at rtfor 1 h. Then, a solution of 75C in DCM (0.8 mL) followed by pyridine(0.023 mL, 0.288 mmol) were added and stirred at rt for 5 h. Thereaction mixture was concentrated and the crude mixture was purifiedusing prep. HPLC to give Example 75 (28.3 mg, 0.043 mmol, 45.1% yield)as an off-white solid. LCMS Anal. Calc'd for C₂₇H₃₀F₆N₂O₅S₂ 640.15.found [M+H] 641.3. ¹H NMR (400 MHz, CDCl₃) δ 7.72 (br. s., 1H), 7.42 (d,J=8.6 Hz, 2H), 7.32 (d, J=3.1 Hz, 1H), 6.91 (d, J=8.8 Hz, 2H), 6.83 (d,J=3.3 Hz, 1H), 6.67 (br. s., 1H), 4.04 (br. s., 2H), 3.96 (t, J=6.2 Hz,2H), 3.64, 3.62 (ABq, J=17.2 Hz, 2H), 3.29 (s, 3H), 2.86 (q, J=7.6 Hz,2H), 2.19-2.04 (m, 2H), 1.84-1.76 (m, 2H), 1.68-1.49 (m, 4H), 1.31 (t,J=7.5 Hz, 3H).

Example 76

(S)-4-(1-Cyclopropyl-1H-pyrazol-3-yl)-N-(4-methoxyphenyl)-2-oxo-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-1,2,5,6-tetrahydropyridine-3-carboxamide

76A.(S)-3-Amino-1-(1-cyclopropyl-1H-pyrazol-3-yl)-4,4,4-trifluoro-3-(4-(4,4,4-trifluorobutoxy)phenyl)butan-1-one:76A was prepared in a similar manner as Example 1A and 1B. LCMS Anal.Calc'd for C₂₇H₃₀F₆N₂O₅S₂, 449.15. found [M+H] 450.1.

76B.(S)—N¹-(4-(1-Cyclopropyl-1H-pyrazol-3-yl)-1,1,1-trifluoro-4-oxo-2-(4-(4,4,4-trifluorobutoxy)phenyl)butan-2-yl)-N³-(4-methoxyphenyl)malonamide:To a solution of 3-((4-methoxyphenyl)amino)-3-oxopropanoic acid (13.97mg, 0.067 mmol) in dichloromethane (1 mL) was added triphenylphosphine(17.51 mg, 0.067 mmol) and trichloroacetonitrile (9.64 mg, 0.067 mmol).After 1 h, 76A (10 mg, 0.022 mmol) in dichloromethane (1 mL) was addedand the reaction was stirred for 16 h. The reaction mixture wasconcentrated and the crude product was purified by flash chromatographyto give 76B (13 mg, 0.020 mmol, 91% yield) as a light yellow oil. LCMSAnal. Calc'd for C₃₀H₃₀F₆N₄O₅, 640.21. found [M+H] 641.3.

Example 76

To a stirred solution of 76B (13 mg, 0.020 mmol) in MeOH (3 mL) wasadded piperidine (10.05 μl, 0.101 mmol) and the reaction was heated to60° C. for 16 h. The reaction mixture was concentrated and purified byprep. HPLC to afford Example 76 (3.5 mg, 0.056 mmol, 28% yield) as alight yellow oil. LCMS Anal. Calc'd for C₃₀H₂₈F₆N₄O₄, 622.20. found[M+H] 623.2. ¹H NMR (500 MHz, DMSO-d₆) δ 10.11 (s, 1H), 9.27 (s, 1H),7.80 (d, J=2.5 Hz, 1H), 7.56-7.48 (m, 4H), 7.08-6.98 (m, 2H), 6.90 (d,J=9.1 Hz, 2H), 6.36 (d, J=2.2 Hz, 1H), 4.06 (t, J=6.2 Hz, 2H), 3.90-3.78(m, 2H), 3.74-3.71 (m, 4H), 2.47-2.31 (m, 2H), 1.99-1.86 (m, 2H),1.16-0.90 (m, 4H).

Example 77((S)-4-(4-Methyl-1H-pyrazol-1-yl)-2-oxo-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-1,2,5,6-tetrahydropyridine-3-carbonitrile

A mixture of 67E (13 mg, 0.030 mmol) and 4-methyl-1H-pyrazole (25.01 mg,0.305 mmol) were heated to 100° C. for 7 min. The reaction mixture wasconcentrated and purified by prep. HPLC to afford Example 77 (12 mg,0.025 mmol, 83% yield). LCMS Anal. Calc'd for C₂₁H₁₈F₆N₄O₂, 472.13.found [M+H] 473.1. ¹H NMR (500 MHz, DMSO-d₆) δ 9.74 (s, 1H), 8.56 (s,1H), 7.93 (s, 1H), 7.57 (d, J=8.8 Hz, 2H), 7.03 (d, J=9.1 Hz, 2H), 4.23(d, J=17.6 Hz, 1H), 4.06 (t, J=6.2 Hz, 2H), 3.89 (d, J=17.9 Hz, 1H),2.46-2.32 (m, 2H), 2.12 (s, 3H), 1.98-1.87 (m, 2H).

1. A compound of Formula (I):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, apolymorph, a solvate or a hydrate thereof, wherein: ring A isindependently a 5- to 6-membered heteroaryl comprising carbon atoms and1-4 heteroatoms selected from N, NR^(e), O and S; wherein saidheteroaryl is substituted with 0-1 R⁶ and 0-2 R⁷; R¹ is independentlyselected from: —(CH₂)_(m)—(C₃₋₆ carbocycle substituted with 0-2 R^(b)and 0-2 R^(g)), —(CH₂)_(m)—(5- to 6-membered heteroaryl comprisingcarbon atoms and 1-4 heteroatoms selected from N, NR^(e), O and S;wherein said heteroaryl is substituted with 0-1 R^(b) and 0-2 R^(g)),and (a C₁₋₁₂ hydrocarbon chain substituted with 0-3 R^(a); wherein saidhydrocarbon chain may be straight or branched, saturated orunsaturated); R² is independently selected from: C₁₋₄ alkyl, C₃₋₄cycloalkyl, and C₁₋₄ haloalkyl; R³ is independently selected from: H, F,C₁₋₄ alkyl and CN; R⁴ is independently selected from: H, F, and C₁₋₄alkyl; R³ and R⁴ may be combined with the carbon atom to which they areattached to form a 3- to 6-membered carbocycle; R⁵ is independentlyselected from: H, halogen, C₁₋₆ alkyl, CN, NO₂, R^(c), NH₂,—(CH₂)_(n)—(X)_(t)—(CH₂)_(m)R^(c), —CONH(C₁₋₆ alkyl), and—NHCOX₁SO₂R^(i); X is independently selected from the group consistingof O, S, NH, CONH, and NHCO; X₁ is independently C₁₋₄ hydrocarbon chainoptionally substituted with C₁₋₄ alkyl or C₃₋₄ cycloalkyl; R⁶ isindependently selected from: halogen, C₁₋₆ alkyl substituted with 0-2R^(h), C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CO(C₁₋₄ alkyl),—(CH₂)_(m)—C₃₋₆ cycloalkyl, —(CH₂)_(m)—NR^(f)R^(i), CN, OR^(i), SR^(i),and (a 4- to 6-membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, NR^(e), O, and S); R⁷ is independentlyselected from: halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, andC₁₋₄ haloalkoxy; alternatively, R⁶ and R⁷, together with the carbonatoms to which they are attached, combine to form a 5- to 6-memberedcarbocyclic ring or a 5- to 6-membered heterocyclic ring comprisingcarbon atoms and 1-3 heteroatoms selected from N, NR^(e), O, and S;wherein said heterocycle is substituted with 0-2 R^(g); R^(a) is, ateach occurrence, independently selected from: halogen, OH, C₁₋₆ alkoxy,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, N(C₁₋₄ alkyl)₂, COOH, and—(CH₂)_(n)—R^(c); R^(b) is, at each occurrence, independently selectedfrom: halogen, OH, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, C₁₋₁₀ haloalkyl, C₁₋₁₀haloalkoxy, C₁₋₁₀ alkylthio, haloalkylthio, N(C₁₋₄ alkyl)₂, —CONH(C₄₋₂₀alkyl), —CONH(C₄₋₂₀ haloalkyl), —O(CH₂)_(s)O(C₁₋₆ alkyl),—O(CH₂)_(s)O(C₁₋₆ haloalkyl), R^(c), and—(CH₂)_(n)—(O)_(t)—(CH₂)_(m)R^(c); R^(c) is, at each occurrence,independently selected from: C₃₋₆ cycloalkyl substituted with 0-2 R^(d),C₃₋₆ cycloalkenyl substituted with 0-2 R^(d), —(CH₂)_(m)-(phenylsubstituted with 0-3 R^(d)), and a 5- to 6-membered heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from N, NR^(e), O,and S; wherein said heterocycle is substituted with 0-2 R^(d); R^(d) is,at each occurrence, independently selected from: halogen, OH, CN, NO₂,C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, tetrazolyl,OBn and phenyl; R^(e) is, at each occurrence, independently selectedfrom: H, C₁₋₈ alkyl, C₁₋₈ haloalkyl, —(CH₂)_(n)—C₃₋₆ carbocycle, CO(C₁₋₄alkyl) and COBn; R^(f) is, at each occurrence, independently selectedfrom: H and C₁₋₄ alkyl; R^(g) is, at each occurrence, independentlyselected from: halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, andC₁₋₄ haloalkoxy; R^(h) is, at each occurrence, independently selectedfrom: OH, halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, and C₁₋₄haloalkoxy; R^(i) is, at each occurrence, independently selected fromthe group consisting of C₁₋₄ alkyl, C₃₋₄ cycloalkyl and phenyl; n, ateach occurrence, is independently 0 or 1; m, at each occurrence, isindependently 0, 1, 2, 3, or 4; s, at each occurrence, is independently1, 2, or 3; and t, at each occurrence, is independently 0 or
 1. 2. Acompound according to claim 1, wherein: R¹ is independently selectedfrom: (C₃₋₆ carbocycle substituted with 0-2 R^(b) and 0-2 R^(g)), (a 5-to 6-membered heteroaryl comprising carbon atoms and 1-4 heteroatomsselected from N, NR^(e), O and S; wherein said heteroaryl is substitutedwith 0-1 R^(b) and 0-2 R^(g)), and (a C₁₋₁₂ hydrocarbon chainsubstituted with 0-1 R^(a); wherein said hydrocarbon chain may bestraight or branched, saturated or unsaturated); R³ is independentlyselected from: H, F, C₁₋₄ alkyl and CN; R⁴ is independently selectedfrom: H, F, and C₁₋₄ alkyl; R^(b) is, at each occurrence, independentlyselected from: halogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, C₁₋₁₀ haloalkyl,C₁₋₁₀ haloalkoxy, C₁₋₁₀ alkylthio, haloalkylthio, N(C₁₋₄ alkyl)₂,—CONH(C₄₋₂₀ alkyl), —CONH(C₄₋₂₀ haloalkyl), —O(CH₂)_(s)O(C₁₋₆ alkyl),—O(CH₂)_(s)O(C₁₋₆ haloalkyl), and —(CH₂)_(n)—(O)_(t)—(CH₂)_(m)R^(c); andR^(d) is, at each occurrence, independently selected from: halogen, C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, tetrazolyl, OBn andphenyl.
 3. A compound according to claim 1, wherein: ring A isindependently selected from: pyrrolyl, thienyl, thiazolyl, pyrazolyl,pyridyl, and pyrimidinyl; wherein each ring moiety is substituted with0-1 R⁶ and 0-2 R⁷; and alternatively, R⁶ and R⁷, together with thecarbon atoms to which they are attached, combine to form a 6-memberedcarbocyclic ring.
 4. A compound according to claim 1, wherein: ring A isindependently selected from:

R¹ is independently selected from: (phenyl substituted with 1 R^(b) and0-2 R^(g)),

and a C₁₋₁₂ hydrocarbon chain substituted with 0-1 R^(a); wherein saidhydrocarbon chain may be straight or branched, saturated or unsaturated;R² is independently selected from: C₁₋₄ alkyl and C₁₋₄ haloalkyl; R³ isindependently selected from: H and F; R⁴ is independently selected from:H and F; R⁵ is independently selected from: CN, NH₂, —CONH(C₁₋₆ alkyl),R^(c), —CONHSO₂(C₁₋₄ alkyl), —NHCOCH₂SO₂(C₁₋₄ alkyl), —NHCONH(C₁₋₄alkyl), —OCONH(C₁₋₄ alkyl), and —CONH(Ph substituted with 0-1 R^(g)); R⁶is independently selected from: halogen, C₁₋₄ alkyl substituted with 0-1N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and C₃₋₆ cycloalkyl; R⁷ is independentlyselected from: halogen, C₁₋₄ alkyl and C₁₋₄ alkoxy; R^(a) is, at eachoccurrence, independently selected from: halogen, OH, C₁₋₄ alkoxy, C₁₋₄haloalkyl, and C₁₋₄ haloalkoxy; R^(b) is, at each occurrence,independently selected from: halogen, OH, C₁₋₈ alkyl, C₁₋₈ alkoxy, C₁₋₈haloalkyl, and C₁₋₁₀ haloalkoxy; R^(c) is a 5- to 6-membered heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from N, NR^(e), O,and S; R^(g) is, at each occurrence, independently selected from:halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;m, at each occurrence, is independently 0, 1, 2 or 3; and s, at eachoccurrence, is independently 1, 2, or
 3. 5. A compound of Formula (IIa)or (IIb):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, apolymorph, a solvate or a hydrate thereof, within the scope of any ofthe above aspects, wherein: R¹ is independently selected from:

and (a C₁₋₁₂ hydrocarbon chain; wherein said hydrocarbon chain may bestraight or branched, saturated or unsaturated); R² is independentlyselected from: CF₃ and CH₃; R⁵ is independently selected from: CN,tetrazolyl, —CONHSO₂(C₁₋₄ alkyl), —NHCOCH₂SO₂(C₁₋₄ alkyl), and—CONH(4-C₁₋₄ alkoxy-Ph); R⁶ is independently selected from: halogen,C₁₋₄ alkyl substituted with 0-1 N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and C₃₋₆cycloalkyl; R^(b) is independently selected from: —O(CH₂)₁₋₆CF₃, and—O(CH₂)₁₋₄CF₂CF₃; R^(e) is independently selected from: —(CH₂)₁₋₆CF₃,and —(CH₂)₀₋₁(C₃₋₆ cycloalkyl); and R^(g) is independently selectedfrom: halogen and C₁₋₄ alkoxy.
 6. A compound according to claim 5,wherein: R¹ is


7. A compound according to claim 1, wherein the compound is selectedfrom the exemplified examples or a stereoisomer, a tautomer, apharmaceutically acceptable salt, a polymorph, a solvate or a hydratethereof.
 8. A pharmaceutical composition, comprising a pharmaceuticallyacceptable carrier and a compound of claim
 1. 9. A compound of claim 1,wherein the compound has hMGAT2 IC₅₀ values≦1 using the MGAT2 LCMSassay.
 10. A compound of claim 1, wherein the compound has hMGAT2 IC₅₀values≦0.5 using the MGAT2 LCMS assay.
 11. A compound of claim 1,wherein the compound has hMGAT2 IC₅₀ values≦0.1 using the MGAT2 LCMSassay.
 12. A pharmaceutical composition comprising a compound accordingto claim 1 and further comprising a dipeptidyl peptidase-IV (DPP4)inhibitor.
 13. A method of treating a disease or disorder associatedwith the activity of the MGAT2 by administering at least one compoundaccording to claim
 1. 14. A method of treating at least one disease ordisorder selected from the group consisting of diabetes, hyperglycemia,impaired glucose tolerance, gestational diabetes, insulin resistance,hyperinsulinemia, nonalcoholic fatty liver disease (NAFLD) includingnonalcoholic steatohepatitis (NASH), retinopathy, neuropathy,nephropathy, delayed wound healing, atherosclerosis and its sequelae,abnormal heart function, myocardial ischemia, stroke, MetabolicSyndrome, hypertension, obesity, dyslipidemia, dyslipidemia,hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, lowhigh-density lipoprotein (HDL), high low-density lipoprotein (LDL),non-cardiac ischemia, lipid disorders and/or glaucoma with a compoundaccording to claim 1.